Drug Elimination & Hepatic Clearance (BSPH-3101) - SE PDF

Summary

This document provides notes on drug elimination and hepatic clearance, covering topics such as routes of drug administration, sites of metabolism, factors affecting elimination, variability in elimination half-lives, renal drug excretion, first-order elimination, and hepatic clearance.

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BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ ROUTE OF DRUG ADMINISTRATION &...

BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ ROUTE OF DRUG ADMINISTRATION & - Nonrenal drug elimination is usually EXTRAHEPATIC DRUG METABOLISM assumed to be due for the most part to Drug Elimination: hepatic metabolism ○ Decline in peak plasma concentrations is due to drug elimination. Metabolism rate constant (km) ○ Involves metabolism (biotransformation) - is the sum of the rate constant for the and renal excretion. formation of each metabolite - since a drug may be biotransformed to Sites of Metabolism: several metabolites ○ Principal site: liver. - The equation assumes that the process of ○ Other sites: lung, skin, gastrointestinal metabolism (at low drug conc) is first-order, mucosal cells, microbiological flora in the and that the substrate conc is very low distal ileum, large intestine, and kidney. - Drug conc at therapeutic plasma levels (for most drugs) are much lower than the Factors Affecting Drug Elimination: Michaelis-Menten constant (KM), and do not ○ Changes in elimination can be influenced saturate the enzymes involved in metabolism by renal disease, hepatic disease, or drug–drug interactions. % drug metabolized = (km/k) x 100 ○ Measurement of the fraction of drug eliminated by metabolism or excretion FRACTION OF DRUG EXCRETED UNCHANGED helps predict these changes. & FRACTION OF DRUG METABOLIZED Fraction of dose eliminated unchanged (fe) and Variability in Elimination Half-Lives: fraction of dose eliminated as metabolites can be ○ Highly metabolized drugs (e.g., determined for most drugs. phenytoin, theophylline, lidocaine) For many drugs, the literature has show large intersubject variability due to approximate values for the fraction of drug genetic and environmental factors. (fe) excreted unchanged in the urine ○ Less variability for drugs primarily eliminated by renal excretion. Practical Focus If the renal excretion pathways become impaired Renal Drug Excretion: (in kidney disorders), then less drug will be ○ Dependent on glomerular filtration rate excreted renally and hepatic metabolism (in (GFR) and kidney blood flow. liver) may become the primary drug elimination ○ GFR is relatively constant in individuals route. with normal renal function, leading to less The reverse is true if liver function declines. variability in elimination for drugs excreted unchanged in urine. HEPATIC CLEARANCE Is defined as the volume of blood that perfuses FIRST-ORDER ELIMINATION the liver which is cleared of rug per unit of time Rate of Constant Elimination (k) Is the process by which the liver removes drugs - is the sum of the first-order rate constant for from the blood (metabolism and excretion) metabolism (km) and the first-order rate constant for excretion (ke) Total Body Clearance (ClT) - Is composed of all clearances in the body k = ke + km - CLEARANCE refers to the volume of blood/plasma from which a drug is Excretion rate constant (ke) completely removed per unit time - is easily evaluated for drugs that are - Is a measure of how efficiently the primarily renally excreted body can eliminate a drug Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ ClT = Clnr + Clr where: Clnr → nonrenal clearance (aka Clh) Clr → renal clearance Therefore, hepatic clearance is estimated as the difference between body clearance and renal clearance. EXTRAHEPATIC METABOLISM Where few drugs (i.e. NTG) are metabolized extensively outside the liver To measure, calculate the hepatic and renal clearance of the drug, and compare these clearances to ClT ENZYME KINETICS: MICHAELIS-MENTEN EQUATION BIOTRANSFORMATION AKA Metabolism Is the enzymatic conversion of a drug to a metabolite ○ In the body, metabolic enzymatic conc is constant at a given site, and the drug conc may vary When drug conc is low, there are other enzymes to catalyze the rxn Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ ○ Its rate of metabolism is a first-order Michaelis constant (KM) process - Is defined as the substrate conc when the velocity of the rxn is equal to one-half the Saturation of the enzyme maximum velocity (or 0.5Vmax) Occurs when - Is a useful parameter that reveals the conc ○ Plasma drug conc is relatively high of the substrate at which the rxn occurs at ○ All enzyme molecules become half Vmax complexed with drug ○ The rxn rate is at maximum rate NOTE: For drugs with large KM, a higher conc will In turn, the rate process then becomes a be necessary before saturation is reached. zero-order process The relationship of the rate of metabolism to the drug Maximum Reaction Rate (Vmax) and the substrate. conc is a nonlinear, hyperbolic curve drug conc at which the rxn occurs at the half maximum rate Lineweaver-Burk Equation - Corresponds to a composite parameter (KM) - Helps to determine important parameters of enzyme activity by plotting the reciprocal of the reaction rate against the reciprocal of the substrate conc - This plot creates a straight line, making it easier to analyze enzyme kinetics and identify different types of enzyme inhibition KINETICS OF ENZYME INHIBITION E.g. drug is cimetidine An inhibitor may decrease the rate of drug Enzyme kinetics generally considers that 1 mol of metabolism by several different mechanisms drug interacts with 1 mol of enzyme → to form an ○ May combine with a cofactor (i.e. enzyme-drug intermediate. NADPH2) ○ May interact with the drug/substrate The enzyme-drug intermediate then reacts to yield a ○ May interact directly with the enzyme reaction product or a drug metabolite. Enzyme inhibition can be reversible or irreversible ○ Its mechanism can be classified by Michaelis-Menten Equation enzyme kinetics studies and observing - Describes the rate process for drug changes in KM and Vmax metabolism - Assumes that the rate of an enzymatic reaction is dependent on the concs of both the enzyme and the drug that an energetically favored drug-enzyme intermediate is initially formed - However, enzymes may catalyze more than one drug molecule (multiple sites) at a time When all the enzyme is saturated, the reaction rate is dependent on the availability of free enzymes, and the reaction rate proceeds at zero-order maximum velocity. Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ Non-competitive Enzyme Inhibition The inhibitor may inhibit the enzyme by combining at a site on the enzyme that is different from the active site (i.e. allosteric site) Depends only on the inhibitor concentration Cannot be reversed by increasing the drug conc, since the inhibitor will interact strongly with the enzyme and will not be displaced by the drug KM is not altered, but Vmax is lower Competitive Enzyme Inhibition The inhibitor and drug-substrate compete for the same active site on the enzyme Drug and inhibitors have similar chemical structures An increase in drug cinc may displace the inhibitor from the enzyme, and partially or fully reverse the inhibition Is observed by a change in the KM, but the Vmax remains the same Clinical Example Pravastatin sodium (PravacholⓇ) is a statin (HMG-CoA reductase inhibitor) that reduces cholesterol biosynthesis. The FDA label warns of increased myopathy risk when used with erythromycin, cyclosporine, niacin, or fibrates. However, no significant myopathy or CPK level increases were observed in 100 post-transplant patients treated with pravastatin and cyclosporine for up to 2 years. Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ PHARMACOKINETICS KINETICS OF ENZYMATIC INHIBITION OR Pravastatin has variable bioavailability (CV MACROMOLECULE-BINDING INHIBITION IN of 50-60% for AUC). VITRO Average oral absorption is 34%, with an Competitive Inhibition: absolute bioavailability of 17%. Involves an enzyme or macromolecule (e.g., Undergoes extensive first-pass extraction in transport protein) and an inhibitor. the liver (extraction ratio 0.66). In vitro screening assays are used to CYCLOSPORINE INTERACTION evaluate potential inhibitors. Cyclosporine significantly increases pravastatin levels by inhibiting hepatic IC50: transporters, affecting both plasma and Represents the inhibitor concentration that liver concentrations. reduces enzymatic or macromolecule-ligand Changes in hepatic uptake have a minimal binding activities by 50%. effect on liver concentration but significantly Dependent on concentrations of enzyme, alter plasma levels. Changes in canalicular efflux significantly inhibitor, substrate, and experimental affect liver concentration but have a small conditions. impact on plasma levels. Ki Value: CONCLUSION An intrinsic, thermodynamic quantity Pravastatin’s therapeutic goal is to optimize independent of the substrate but dependent liver concentrations while minimizing on the enzyme and inhibitor. exposure at unintended sites to avoid More accurate for determining inhibition. adverse effects like myopathy. Drug-drug interactions should be carefully managed, and alternative agents with fewer Software Development: interactions may be recommended. Cer et al. (2009) developed software to compute Ki values from IC50 NOTE measurements. A drug that is metabolized and also subject to the efflux effect of hepatic transporters can affect IC50 AND AFFINITY overall plasma drug and liver drug concs. However, Cheng–Prusoff Equation: plasma drug concs are not the only considerations. ○ Describes the relationship between the 50% inhibition concentration (IC50) and Drug-drug interaction should be avoided/minimized the inhibition constant (Ki). with a wash-out period during coadministration. ○ Ki represents the binding affinity of the Alternative therapeutic agents with less liability for inhibitor, while IC50 indicates the DDI may be recommended. functional strength of the inhibitor. ○ When substrate concentration [D] is much Sensitivity analyses less than KM, Ki equals IC50. When [D] - Changes in hepatic uptake ability altered equals KM, Ki equals IC50/2. the plasma conc of pravastatin markedly, but had a minimal effect on the liver conc IC50 vs. Ki: - Whereas, changes in canalicular efflux ○ IC50 values can vary between altered the liver conc of pravastatin experiments due to different conditions. markedly but had small effect on the ○ Ki is an absolute value, representing the plasma conc concentration of inhibitor needed to occupy 50% of the enzyme in the absence Conclusion: Changes in the OATP1B1 of competing ligand. (transporter) activities may have a small impact on the therapeutic efficacy and a large impact on the side effect (myopathy) of pravastatin, respectively. Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ Application in Pharmacology: The major short-coming of compartment ○ Used to determine Ki for competitive modeling is the lack of realistic physiologic inhibitors on enzymes or macromolecules information like transporters. However, they are still useful for predicting drug ○ Important to consider the ratio of inhibition metabolite plasma levels concentration to IC50 ([I]/IC50) during drug development to assess potential Practice Problem interactions. Drug Development Considerations: ○ Interactions with [I]/IC50 > 0.1 should be investigated early in drug development. ○ FDA provides guidelines and updates on studying drug metabolism inhibition/induction and drug-drug interactions (DDI) METABOLITE PHARMACOKINETICS FOR DRUGS ONE-COMPARTMENT MODEL May be used to estimate simultaneously both metabolite formation and drug decline in the plasma Example: a drug is given IV bolus inj, and then metabolized by parallel pathways ASSUME: both metabolite formation and metabolite and parent drug elimination follow linear (first-order) pharmacokinetics at therapeutic considerations The rate of elimination of the metabolite may be faster or slower than the rate of formation of the metabolite from the drug ○ Metabolites (i.e. glucuronide, sulfate, or glycine conjugates) are more polar and eliminated faster than parent drug. ○ Less polar metabolites (e.g., acetylated) are eliminated slower, leading to potential accumulation. Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ - the equation for metabolite plasma conc (Cm) is triexponential, calculated from the various kinetic constants (Vm) and the dose of the drug ANATOMY AND PATHOPHYSIOLOGY OF THE LIVER TWO-COMPARTMENT MODEL Cephalothin - An antibiotic drug - Is rapidly metabolized by hydrolysis (in human and rabbits) - Its metabolite, desacetylcephalothin, has less antibiotic activity - Follows one-compartment modeling - In human urine, 18-33% of the drug was recovered in metabolite form - This drug follows two-compartment model after IV bolus inj in rabbit - It declines as a result of excretion and metabolism Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ removal before the blood enters the general circulation ○ These are lined with endothelial cells or Kupffer cells (are phagocytic tissue macrophages that are part of the reticuloendothelial system), which engulf worn-out RBC and foreign material The common bile duct drains bile and biliary excretion products from both lobes into the gallbladder The principal sites of liver metabolism are the hepatocytes ○ But drug transporters (influx or efflux) are also present aside from CYP isoenzymes LIVER is the major organ responsible for drug metabolism Is both a synthesizing and an excreting organ Its basic anatomical unit is the liver lobule, which contains parenchymal cells Consists of large right and left lobes that merge in the middle ○ Secretes bile acids within the lobes, which flows through a Drug Metabolism in the Liver Are flow- and site-dependent network of channels, and into the The quantity of enzyme involved in metabolizing common bile duct drug is not uniform throughout the liver Is perfused by blood from the hepatic activity Cirrhosis (hepatic disease) can cause tissue ○ The large hepatic portal vein that fibrosis, necrosis, and hepatic shunt, resulting in collects blood from various changing blood flow and changing bioavailability segments of the GIT also perfuses of drugs in the liver The half-lives of drugs in this metabolism are HEPATIC ARTERY carries oxygen to the variable liver (25% of the liver blood supply) A pharmacokinetic model simulating hepatic HEPATIC PORTAL VEIN carries nutrients to metabolism involve the ff elements: the liver (75% of the liver blood flow); where ○ The heterogeneity of the liver blood leaves, and empties into the vena ○ The hydrodynamics of hepatic blood flow cava ○ The nonlinear kinetics of drug metabolism The terminal branches of both hepatic artery ○ Any unusual or pathologic condition of the and vein fuse within the liver and mix with subject the large vascular capillaries (sinusoids) Average hepatic blood flow = 1.3-1.5 L/min ○ Sinusoids are blood vessels that ○ Ex: Hepatic arterial blood flow and hepatic from a large reservoir of blood, venous blood enter the liver at different facilitating drug and nutrient flow rates, and their drug conc are different Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ ○ Results assume that a toxic metabolite ○ catalyzes the biotransformation of various may be transiently higher in some liver endogenous compounds tissues ○ located in other tissues i.e. kidney, GIT, skin, and lungs HEPATIC ENZYMES INVOLVED IN THE ○ is absent in some/few enzymatic oxidation BIOTRANSFORMATION OF DRUGS reactions, including the monoamine MIXED-FUNCTION OXIDASE oxidase (MAO) The type of metabolism is based on the reaction It deaminates endogenous involved substrates including NTs The most common reactions are: ○ Oxidation Examples of MAO interaction: ○ Reduction → alcohol and aldehyde dehydrogenase in the ○ Hydrolysis soluble fraction of liver are involved in the metabolism ○ Conjugation of ethanol and xanthine oxidase, which converts hypoxanthine to xanthine and then to uric acid. Mixed-function Oxidase (MFOs) ○ Monoxygenase enzymes, which are Drug substrates for xanthine oxidase include responsible for oxidation and reduction theophylline and 6-mercaptopurine. of drugs ○ Are structural enzymes that constitute an Allopurinol electron-transport system that requires: - A substrate and inhibitor of xanthine oxidase Reduced NADPH (NADPH2) - It delays metabolism of other substrate used Molecular oxygen in tx of gout CYP450 NADPH-CYP450 reductase DRUG BIOTRANSFORMATION REACTIONS Phospholipid Theophylline, phenytoin, acetaminophen, among others, have a direct relationship between Phospholipid → involved in the binding of the drug the rate of drug metabolism and the elimination molecule to the CYP450 and coupling the half-life for the drug NADPH-CYP450 reductase to the CYP450 The conversion of a drug to a more polar CYP450 → is a heme protein with iron protoporphyrin metabolite enables the drug to be eliminated IX; is the terminal component of an electron-transfer more quickly (HIPE) system in the ER, acting as both an oxygen- and The ff can influence the type of drug metabolism substrate-binding locus; consists of closely related formed: isoenzymes (differ in amino acid sequence and drug ○ Nature of the drug specificity) ○ Route of administration Hepatic parenchymal cells contain MFOs, in association with the endoplasmic reticulum → Examples: which is a network of lipoprotein membranes 1. Isoproterenol within the cytoplasm and continuous with the - Given orally, forms a sulfate cellular and nuclear membranes conjugate in the GI mucosal cells ○ when fragmented and centrifuged, a - Given IV, forms the 3-O-methylated microsomal fraction (microsome) is metabolite via obtained from the supernatant S-adenosylmethionine and ○ this fraction contains fragments of the ER catechol-O-methyltransferase Many lipid-soluble drugs bind to CYP450 2. Sulfasalazine (Azo drugs) results to oxidation - Poorly absorbed after oral CYP monooxygenase enzyme system administration Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ - However, is cleaved by the intestinal microflora, producing 5-aminosalicylic acid and sulfapyridine, which is absorbed in the lower bowel The biotransformation of drugs can be classified acc to: ○ The pharmacologic activity of the metabolite ○ The biochemical mechanism for each biotransformation reaction parent drug → metabolize → inactive → elimination PATHWAYS OF DRUG BIOTRANSFORMATION Metabolites may be pharmacologically active Divided in two major groups: Phase I and Phase or produce toxic effects II A number of drugs that resemble natural PRODRUGS biochemical molecules are able to utilize the - are inactive metabolic pathways for normal body compounds. - must be biotransformed in the body to Examples include: metabolites that have pharmacological ○ Isoproterenol → methylated by COMT activity ○ Amphetamine → deaminated by MAO - recently, are designed to improve stability, ○ Both COMT and MAO are involved in increases systemic absorption, or prolong metabolizing norepinephrine the duration of activity PHASE I REACTIONS 1. Prontosil Aka Asynthetic reactions - Is reduced to the antibacterial agent Reactions include: oxidation, reduction and sulfanilamide hydrolysis 2. Levodopa Occurs first and introduce or expose a functional - An antiparkinson agent group on the drug molecules - Crosses the BBB, then decarboxylated in the brain to Phenylbutazone L-dopamine (an active NT) - Rxn: aromatic hydroxylation - LD does not easily - Where oxygen is introduced in its phenyl penetrate the BBB, group therefore cannot be used - Forms oxyphenbutazone (a more polar as a therapeutic agent metabolite) Codeine - Demethylated to form morphine Aspirin and benzocaine - Hydrolysis of ester - Yields more polar products - Aspirin → salicylic acid - Benzocaine → p-aminobenzoic acid Acetaminophen benzo[a]pyrene Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ - Hydroxylation reaction May demonstrate nonlinear kinetics at very - These have aromatic rings high drug conc - Reactive ingredients, i.e. epoxides, are formed Glycine, sulfate, and glutathione conjugations - Are highly reactive Have lesser capacity - Will react with macromolecules Demonstrates kinetics at therapeutic drug - Causing liver necrosis (APAP) or conc cancer (benzo[a]pyrene) The limited capacity of certain conjugation pathways Salicylic acid may be due to the ff factors: - Can be conjugated directly (phase II) without 1. Limited amount of the conjugate transferase a preceding phase I reaction 2. Limited ability to synthesize the active nucleotide intermediate PHASE II REACTIONS 3. Limited amount of conjugating agent (i.e. Aka Synthetic / Conjugation reaction glycine) Occurs once a polar constituent is revealed or placed into the molecule N-acetylated conjugation reaction Very common phase II reactions include Shows genetic polymorphism glucuronidation and sulfate conjugation, that The human population may be divided into result in water-soluble metabolites being rapidly fast and slow acetylators excreted in bile and/or urine Some may be diminished or defective in Phase II reactions often implicated in drug toxicity cases of inborn errors of metabolism are acetylation and mercapturic acid synthesis Rxns implicated with drug toxicity: Phase II rxns use conjugating reagents, which Acetylation are derived from biochemical compounds Its product is usually less polar than the parent involved in carbohydrate, fat, and protein drug metabolism Example drugs under this reaction include ○ Uridine diphosphoglucuronic acid sulfanilamide, sulfadiazine, and sulfisoxazole (UDPGA) ○ In sufficient conc, precipitate in the kidney ○ Acetyl CoA tubules, causing kidney damage and ○ 3’-phosphoadenosine-5’phosphosulfate crystalluria (PAPS) ○ Moreover, a less polar metabolite is ○ S-adenosylmethionine (SAM) reabsorbed in the renal tubule and has longer elimination half-life The drug may also be activated to a high-energy compound that then reacts with the conjugating Procainamide agent in the presence of a transferase enzyme - Acetylated to N-acetylprocainamide - is biologically active - elimination half-life of 6-7 hours Salicylic acid - Conjugated with glycine, to form salicyluric Isoniazid acid or glucuronic acid, to form - Also acetylzed by N-acetyltransferase salicylglucuronide enzyme - Demonstrates genetic polymorphism Some reactions may have limited capacity at high - 2 distinct subpopulations have been drug conc, leading to nonlinear drug metabolism observed to inactive isoniazid, including: - Slow inactivators → adverse Glucuronidation reaction effect of peripheral neuritis occurs Have a high capacity - Rapid inactivators Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ ➔ S-carprofen glucuronide has predominate Glutathione and Mercapturic Acid Conjugation activity as its clearance through the kidney is Is a tripeptide of glutamyl-cysteine-glycine faster, than the R-form (36 mL/min) Is involved in many important biochemical reactions Mephenytoin Is important in the detoxification of reactive ➔ Both R and S enantiomers are metabolized oxygen intermediates into nonreactive by hydroxylation in humans metabolites ◆ It reduces the lipophilicity and Is the main intracellular molecule for protection of reduce partition into the CNS the cell against reactive electrophilic compounds Reacts nonenzymatically and enzymatically via ➔ After oral does of 300 mg, the plasma conc the enzyme glutathione S-transferase of the S-form was only about 25% of that of the R-form GSH conjugates ➔ S-form elimination half-life is faster/shorter - are precursors for a group of drug (2.13 hrs < 76 hrs) conjugates known as mercapturic acid ➔ Severity of side effects is less in px with (N-acetylcysteine) derivatives rapid metabolism - Are saturable A review shows that of 475 semisynthetic drugs Acetaminophen derived from natural sources, 469 were enantiomers. - May form electrophilic intermediates - It bonds to hepatic cellular macromolecules, resulting in cellular injury and necrosis - Also depletes GSH in the cell - Suggested antidote is N-acetylcysteine (Mucomyst) - Contains sulfhydryl (R-SH) groups METABOLISM OF ENANTIOMERS Each isomeric form of a drug may have different pharmacologic actions and side effects Thyroid hormone REGIOSELECTIVITY ➔ natural = l-thyroxine → stimulates metabolic When the enzymes catalyze a reaction that is rate only specific for a particular region in the drug ➔ synthetic = d-thyroxine → lowers molecule cholesterol only Isoproterenol Many drugs are now available as pure - Methylated via catechol-O-methyltransferase enantiomers and S-adenosylmethionine in meta position - Results in 3-O-methylated metabolite Disopyramide - Very little methylation occurs at the hydroxyl ➔ (S)-(+)disopyramide → more highly bound group in the para position in humans than (R) ➔ (R)-(-)disopyramide Carprofen ➔ An NSAID Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ SPECIES DIFFERENCES IN HEPATIC Macro models based on mass balance are kinetically BIOTRANSFORMATION ENZYMES based and the amount of drug in the plasma pool can still be computed and properly tracked. VARIATION OF BIOTRANSFORMATION ENZYMES Genetic Differences PHARMACOGENETICS The study of genetic differences in pharmacokinetics and pharmacodynamics Isoniazid - Undergoes N-acetylation - Is genetically determined with 2 identifiable groups (aka genetic polymorphism): rapid and slow acetylators Preclinical phase studies attempt to identify the - Slow acetylators are prone to major metabolic pathways of a new drug through isoniazid-induced neurotoxicity using different animal models In others, rate of metabolism may differ among Other drugs that are acetylated include diff animal species even though the procainamide and hydralazine. biotransformation pathways are the same An example of genetic difference is glucose Amphetamine 6-phosphate-dehydrogenase deficiency, observed - Mainly hydroxylated in rats in 10% African-Americans, with the drug phenytoin. - Is largely deaminated in humans and dogs Phenytoin In recent years, in vitro drug screening with - Where two phenotypes were identified human liver microsomes or with hepatocytes - Efficient Metabolizer (EM) has helped confirm whether a given CYP - Poor Metabolizer (PM); in Japanese isoenzyme is important in human drug (16%) and Caucasians (4%) metabolism Mephobarbital DRUG INTERACTION - Side effects were higher in Japanese Lovastatin subjects - (MevacorⓇ) - Due to a slower oxidative metabolism - A cholesterol-lowering agent - Metabolized by human liver into two: Propranolol - 6'b-hydroxy lovastatin and - Metabolism is also different among Chinese 6’-exomethylene lovastatin population - 6'b-hydroxy lovastatin formation was inhibited by the specific CYP3A inhibitors NOTE: Some variations in metabolism may be related cyclosporine, ketoconazole, and to geographic rather than racial differences. troleandomycin - Cyclosporine produces a DDI Environmental Factors and Exposure to Chemical based on the review of Ki values Theophylline - In addition to CYP3A inhibitors, an efflux - Half-life is shooter due to smoking transporter can deplete the drug before - Since benzpyrene are released which biotransformation stimulate the enzymes involved - HYDROXYLATION (Phase 1) occurs, and - Young children are also known to eliminate catalyzed by CYP450 enzyme CYP3A this drug more quickly Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ Phenobarbital - A potent inducer of wider variety of hepatic enzymes 3-methylcholanthrene and benzpyrene - Also induces hepatic enzyme formation - Are carcinogenic Variety of Agents Hepatic enzymes may also be inhibited by a variety of agents: ○ Carbon monoxide ○ Heavy metals ○ Imidazole drugs (cimetidine) The substrate specificity of CYP450 appear due to: Leads to higher plasma levels Nature of amino acid residues Longer elimination, coadministered Size of the amino acid side chain with phenytoin or theophylline Polarity and charge of the amino acids Physiologic Conditions of the Host CYP1A2 Oxidation of caffeine Age Gender CYP2D6 Oxidation of drugs (codeine, Nutrition propranolol, dextromethorphan) Diet Is responsible for debrisoquine Pathophysiology metabolism among individuals showing genetic polymorphism CYP450 Isoenzymes CYP450 enzyme is the most important enzymes Some drugs metabolized are or the variation in phase 1 metabolism of drugs codeine, flecainide, dextromethorphan, imipramine, ○ Exists in many forms among individuals and other cyclic antidepressants. due to genetic differences ○ Were identified acc to the substrate that CYP3A Metabolizes vindesine, was biotransformed vinblastine, and other vinca alkaloids Isozymes refer to multiforms of CYP450 ○ Are classified into families (roman Vinca alkaloids used in cancer tx numerals) and subfamilies (letters), based have shown great inter- and intraindividual variabilities on the similarity if the amino acid sequences CYP 1-3 Are best known for metabolizing ○ If amino acid sequence is ≥60% similar = clinically useful drugs in humans family Within the family, if amino acid There are now at least 8 families of CYP isozymes sequence is 70% similar = subfamily known in humans and animals. NEW NOMENCLATURE Pharmacokinetic experiments using a “marker” *starts with CYP, and Arabic numbers drugs i.e. antipyrine or dextromethorphan may be used to determine if the intrinsic hepatic clearance of the px is significantly diff from the average subject Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ ❖ Poor metabolizers → lack functional CYP2D6 ❖ Efficient metabolizers → quinidine blocks CYP2D6 so that genotypic EM pxs appear to be phenotypic PM pxs ❖ The inability to metabolize substrates for CYP2D6 results in increased plasma conc of the parent drug in PM pxs DRUG INTERACTIONS INVOLVING DRUG METABOLISM DIET Enzymes involved in metabolism may be altered by: Also affects drug-metabolizing enzymes ➔ Diet, and; Theophylline plasma conc and clearance in ➔ Coadministration of other drugs and px on high-protein diet are lower, than to chemicals those with carbohydrate-diet Sucrose/glucose + fructose decrease the ENZYME INDUCTION activity of MFOs → slower metabolism rate A drug- or chemical-stimulated increase in and prolonged hexobarbital sleeping time in enzyme activity rats ○ Due to an increase in the amount of ○ 5% glucose affect sleeping time in enzyme present px taking barbiturates Requires some onset time for the synthesize of protein Decreased intake of fatty acids - decreased ○ Rifampin → within 2 days basal MFO activities ○ Phenobarbital → within a week ○ Carbamazepine → after 3-5 days, Saquinavir mesylate and is not complete for appx 1 - (InviraseⓇ, Roche) month or longer - A protease inhibitor Smoking can change the rate of metabolism - Has very low bioavailability (4%) of many cyclic antidepressant drugs - AUC increased to 150% when px took it with through enzyme induction 150mL glass of grapefruit juice, then another Some agents include: 150mL glass an hour later ○ Aromatic hydrocarbons - Concentrated grapefruit juice (benzopyrene) → in cigarette increased AUC to 220% smoke - Naringin is partially responsible for ○ Insecticide (chlordane) the inhibition by CYP3A4, resulting ○ Drugs (mentioned above) in creased AUC - Ketoconazole and Ranitidine (ZantacⓇ) also increases saquinavir’s AUC by inhibition ENZYME INHIBITION Due to substrate competition or due to direct of CYP450 inhibition of drug-metabolizing enzymes - Rifampin reduces AUC of saquinavir due to SSRIs have been reported to inhibit enzymatic stimulation CYP2D6 system → result in elevated plasma conc of coadministered psychotropic drugs Sedatives and Coumarin Fluoxetine causes a ten-fold decrease in - Have increased bioavailability when taken the clearance of imipramine and with grapefruit juice desipramine ○ Due to inhibitory effect on hydroxylation Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ Midazolam, buspirone, felodipine, simvastatin, lovastatin → CYP3A Theophylline → CYP1A2 Repaglinide → CYP2C8 S-Warfarin → CYP2C9 Omeprazole → CYP2C19 Desipramine → CYP2D6 Additional examples of substrates, along with inhibitors and inducers of specific CYP enzymes, are listed in Table A-2 in Appendix A in the FDA draft guidance (2006). NOTE: Human over microsomes provide a convenient way to study CYP450 metabolism. Microsomes are a subcellular fraction of tissue obtained by differential high-speed centrifugation Key CYP450 enzymes are collected in the microsomal fraction ○ This enzyme retains their activity for many years in microsomes or whole liver stored at low temperature Hepatic microsomes can be obtained commercially cDNAs for the common CYP450s have been AUTO-INDUCTION & TIME-DEPENDENT cloned PHARMACOKINETICS Recombinant human enzymatic proteins have Auto-induction means drugs changing their own been expressed in a variety of cells metabolism ○ When assessing, the enzyme activity is Pharmacokinetic endpoints recommended for usually measured before and after a assessment of substrates include: period of tx with the inducing agent 1. Exposure measures 2. Pharmacokinetic parameters Time-dependent pharmacokinetics Described with a model where the In-vivo studies are more relied upon for metabolism production rates of the affected enzymes studies. Consideration include: were proportional to the amounts of the 1. Acute or chronic use of the substrate and/or inducing agents and the time course of the interacting drugs induction process was described by the 2. Safety considerations turnover model 3. Pharmacokinetic and pharmacodynamic Example drug is carbamazepine characteristics of the substrate and interacting drugs For new drugs, potential 4. The need to assess induction as well as drug-metabolism/interaction is studied in vitro/vivo by inhibition identifying whether the drug is a substrate for the common CYP450 subfamilies. In practice, an investigational drug under TRANSPORTER-BASED DRUG-DRUG INTERACTIONS development is coadministered with an approved Includes the inhibition or induction of transport drug: proteins Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ ○ Pgp → the most well understood and may be appropriate to evaluate during drug development ○ Organic anion transporter (OAT) ○ Organic anion transporting polypeptide (OATP) ○ Organic cation transporter (OCT) ○ Multidrug resistance-associated proteins (MRP) ○ Breast cancer-resistant protein (BCRP) Interactions include: ○ Digoxin and quinidine ○ Fexofenadine and ketoconazole ○ Penicillin and probenecid ○ Dofetilide and cimetidine Hepatic clearance model Intrinsic clearance here is assumed to be constant within the same subject This model describes how clearance can change in response to physiologic changes Px variability and changes in intrinsic clearance may be due to: ○ Px factors ○ Enzymatic induction / inhibition, due to coadministered drugs ○ Modification of transporters in the liver (P-gp and OATPs) and bile canaliculi Biliary excretion should also be incorporated here NOTE: Knowledge of drug transporters and CYPs can help predict whether many drug interactions have clinical significance. Combined effect of efflux and CYP inhibition can cause serious or even fatal adverse reactions due to several fold increase in AUC or Cmax. FIRST-PASS EFFECT The following can lead to adverse toxicity: Aka presystemic elimination Impairment of bile flow The rapid metabolism of an orally administered Saturation of conjugation enzymes (phase 2) drug before reaching the general circulation Sulfate conjugate formation ○ Oral drugs are absorbed in the duodenal segment of the small intestine and transported via the mesenteric vessels to the hepatic portal vein, and then to the liver, before entering the systemic circulation Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ EVIDENCE OF FIRST-PASS EFFECTS ○ Pathophysiologic condition of the px This may be suspected when there is relatively low concs of parent drug in the systemic Propranolol circulation after oral administration - Requires a higher oral dose than IV dose to ○ AUC of oral drug is also lesser produce equivalent therapeutic blood levels This may also be assumed if the intact drug NOTE: Because liver ERis affected by blood flow to appears in a cannulated hepatic portal vein, but the liver, dosing of drugs with extensive liver not in general circulation metabolism may produce erratic plasma drug levels. For an oral drug with stable in GIT and is 100% systemically absorbed, the AUC should be the Estimation of Reduced BA due to Liver same when the same drug dose is given IV Metabolism and Variable Blood Flow Blood flow to the liver plays an important role in Propranolol, Morphine, NTG the amount of drug metabolized after oral - Drugs that undergo first-pass effect administration - AUC when orally given is smaller than AUC The usual effective hepatic blood flow is 1.5 given IV L/min, but may vary from 1-2 L/min, depending - F0.7) - Are removed by the liver almost as rapidly as the organ is perfused by blood in which blood is contained - Their rate of metabolism is sensitive to changes in hepatic Q - Thus, increase Q = increase rate of drug removal by liver Propranolol - A b-adrenergic drug - Decreases hepatic blow by decreasing cardiac output Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ - Therefore, drug decreases its own clearance through the liver when given orally Factors that may affect the intrinsic clearance for the metabolism of drugs: Smoking (increases IC) INTRINSIC CLEARANCE Changes or alterations in MFOs activity or Used to describe the tidal ability of the liver biliary secretion metabolize a drug in the absence of flow limitations CLEARANCE may be expressed as the rate of drug It reflects the inherent ability of the liver to removal divided by plasma drug conc: metabolize the drug HEPATIC CLEARANCE a concept that characterizes drug elimination And, because the rate of drug removal by the liver is based on both blood flow and the intrinsic is usually the rate of drug metabolism, may be clearance of the liver expressed in terms of hepatic clearance and drug conc entering the liver (Ca): LOW-EXTRACTION RATIO DRUGS When the blood flow to the liver is constant, hepatic clearance is equal (but not constant) to the product of blood flow and the extraction ratio Drugs with low ER and eliminated primarily by HEPATIC CLEARANCE OF A PROTEIN-BOUND DRUG metabolism demonstrate marked variation in Protein-bound drugs are not easily overall elimination half-life metabolized (restrictive clearance). ○ Theophylline → 3-9 hrs (due to genetic Free (unbound) drugs are more readily difference in intrinsic hepatic enzyme metabolized and can diffuse through cell activity) membranes to reach mixed-function oxidase ○ Elimination half-life may also be affected enzymes. by Enzyme induction Impact of Unbound Drug Concentration: Enzyme inhibition ○ An increase in unbound drug Age of px concentration in the blood Nutritional factors enhances hepatic extraction. Pathologic factors Example drugs include theophylline, RESTRICTIVE CLEARANCE phenylbutazone, and procainamide Most drugs like diazepam, quinidine, ○ Their hepatic clearance is less affected by tolbutamide, and warfarin hepatic Q, and more affected by the with clearance proportional to the fraction of intrinsic activity of the MFOs unbound drug (fu) the relationship involves blood flow (Q), intrinsic clearance (Cl’int), and the fraction of unbound drug (fu). ○ When Cl’int is small compared to Q, clearance (Clh) is proportional to fu and Cl’int. ○ When Cl’int is large compared to Q, Clh is dependent on hepatic blood flow and independent of protein binding. Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ NONRESTRICTIVE CLEARANCE High Extraction Ratio (ER) Drugs: Some drugs (e.g., propranolol, morphine, Doubling Cl’int from 13.7 to 27.0 L/min verapamil) increases ER and Cl, but the elimination are cleared by the liver regardless of their half-life decreases only marginally. protein-bound state After oral administration, there is some have a hepatic extraction ratio (ER) greater than decrease in AUC and a moderate shortening the fraction of free drug (fu) and their clearance of t1/2. rate remains unchanged when displaced from binding Impact of Hepatic Enzyme Activity: Protein binding is reversible, and nonrestrictively For drugs with low ER, an increase in bound drugs are more easily “stripped” from hepatic enzyme activity significantly proteins during metabolism. decreases the elimination half-life. For drugs with high ER, the elimination Effects of Protein Binding on Clearance: half-life is not markedly affected by increased ○ Changes in protein binding can enzyme activity due to already high enzyme significantly alter drug clearance for levels. restrictively cleared drugs. Orally administered drugs with higher ER ○ Highly protein-bound drugs (>90%) show a greater first-pass effect, indicated by show increased free drug concentration increased hepatic clearance. and clearance when displaced from binding sites. Effect of Changing Blood Flow in Drugs with High or Low Extraction Ration Impact of Hepatic Blood Flow on Drug Clearance: Effect of Changing Intrinsic Clearance and/or Blood Flow on Hepatic Extraction and Elimination Low Extraction Ratio (E = 0.1): Decreasing Half-Life after IV and Oral Dosing hepatic blood flow from normal (1.5 L/min) to Intrinsic Clearance: Alterations affect the half slightly decreases clearance and slightly elimination half-life of the drug. increases blood levels. Liver Blood Flow: Changes influence the High Extraction Ratio (E = 0.9): Decreasing first-pass effect and bioavailability. hepatic blood flow to half greatly decreases Overall Impact: These factors are represented clearance and significantly increases blood by the area under the curve (AUC) in levels. pharmacokinetic studies. Effect on Elimination: Low Extraction Ratio Drugs (e.g., Effect of Theoretical Change in Clint and F on Drug Clearance theophylline): Elimination is minimally The relationship between blood flow (F), intrinsic affected by changes in hepatic blood flow, as clearance (Cl’int), and hepatic clearance (Cl) was the liver can handle the drug concentration in simulated using hypothetical examples. the blood. The relationship may only apply if all model High Extraction Ratio Drugs (e.g., assumptions are met due to the prevalence of propranolol): Elimination is significantly transporters. affected by changes in hepatic blood flow, making these drugs flow-dependent. Low Extraction Ratio (ER) Drugs: Doubling Cl’int from 0.167 to 0.334 L/min Flow Dependency: increases both ER and Cl, leading to a much Drugs with low extraction ratios are not shorter elimination half-life (t1/2). significantly impacted by changes in blood After oral administration, an increase in Cl’int flow due to the liver’s capacity to eliminate results in decreased area under the curve them. (AUC) and t1/2. Drugs with high extraction ratios are removed from the blood as quickly as they Albano S. C. BSPH-3101 | BIOPHARMACEUTICS AND PHARMACOKINETICS Drug Elimination and Hepatic Clearance 1st SEMESTER | SEMI-FINALS Instructor: Mrs. Jonah Micah T. Jimenez-Madera, RPh _____________________________________________________________________________________________ reach the liver. Reduced blood flow prolongs their elimination. Effect of Changing Protein Binding on Hepatic Clearance Protein Binding and Hepatic Clearance: ○ The effect of protein binding on hepatic clearance is complex and varies depending on whether the drug is restrictively or nonrestrictively cleared. High Extraction Ratio Drugs: ○ For drugs with high extraction ratios, protein binding does not significantly affect hepatic clearance. These drugs are 2. Composition of Bile: flow-limited. ○ Primarily consists of water, bile salts, bile pigments, electrolytes, Low Extraction Ratio Drugs: cholesterol, and fatty acids. ○ For drugs with low extraction ratios, ○ Produced by hepatic cells lining protein binding can influence hepatic the bile canaliculi through active clearance. secretion. ○ If a drug is less than 75% to 80% bound, small changes in protein binding do not 3. Drug Excretion via Bile: significantly affect clearance ○ Drugs with molecular weights >500 (capacity-limited, binding-insensitive). are mainly excreted in bile. ○ Highly bound drugs with low extraction ○ Drugs with molecular weights ratios are sensitive to changes in protein between 300-500 are excreted in binding (capacity-limited, both urine and bile. binding-sensitive). ○ Drugs with molecular weights

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