Pharmacokinetics II: Metabolism and Excretion PDF

Pharmacokinetics II Metabolism, excretion and dosing Steve Evans PhD.  Drug metabolism Process of chemical modification of drug. Almost always carried out by enzymes. Liver is primary site, other organs (e.g. kidneys, lungs and intestine) may be involved to a limited degree with some d...

Pharmacokinetics II Metabolism, excretion and dosing Steve Evans PhD.  Drug metabolism Process of chemical modification of drug. Almost always carried out by enzymes. Liver is primary site, other organs (e.g. kidneys, lungs and intestine) may be involved to a limited degree with some drugs. Most drugs (~70%) undergo metabolism to some extent, most products have less activity than the original compound (parent drug). Some metabolic drug products have more activity , these are known as prodrugs and are often activated in the liver to elicit a therapeutic response (e.g. codeine and clopidogrel). Metabolism to a more water-soluble compound is the fate of many drugs so that they can be readily excreted (via urinary excretion).  The vast majority of drugs are metabolised in the liver by either functionalisation and/or conjugation reactions. It is important to recognise that a drug may: Classification of Be excreted as unchanged parent drug (e.g. gentamicin). drug Undergo functionalisation and be directly metabolism excreted (e.g. caffeine). reactions Undergo conjugation and be directly excreted (e.g. paracetamol). Undergo functionalisation then conjugation prior to excretion (e.g. phenytoin). These reactions are not necessarily sequential and can occur simultaneously (e.g. the metabolism of codeine by oxidation to morphine and by glucuronidation to codeine-6-glucuronide).  Functionalisation reactions Introduction or unmasking of polar (charged) functional group into the molecule to enhance water-solubility. Common functionalization reactions include: Dealkylation (de-ethylation or de-methylation). Hydrolysis. Hydroxylation. Oxidation. Some metabolites might be more active than the parent drug or may be more toxic (case of paracetamol). Cytochrome P450 are a major family of enzymes associated with these reactions. Other functionalization enzymes includes esterases, alcohol dehydrogenase, xanthine oxidase. Cytochrome P450 system Located on the smooth endoplasmic reticulum of cells, particularly abundant in hepatocytes. Metabolism of drugs, environmental pollutants and dietary chemicals. Synthesis of bile acids, hormones and fatty acids. More than 50 individual CYP enzymes, classified based on amino-acid sequence. Families 1,2 and 3 can metabolise drugs, CYP3A4 is the fourth member of CYP family 3 sub-family A. CYPs of greatest importance in human hepatic drug metabolism are: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. CYP450 enzymes cont……. CYP DRUGS METABOLISED CYP1A2 Amitriptyline, caffeine, clozapine, haloperidol, lidocaine (lignocaine), olanzapine, ondansetron, tamoxifen CYP2C8 Chloroquine, montelukast, paclitaxel CYP2C9 Celecoxib, diclofenac, gliclazide, ibuprofen, irbesartan, losartan, naproxen, phenytoin, sildenafil, sulfonylurea, S- warfarin CYP2C19 Citalopram, clopidogrel, diazepam, esomeprazole, omeprazole, pantoprazole, sertraline CYP2D6 Amitriptyline, codeine, dexamfetamine, dextromethorphan, fluoxetine, fluvoxamine, haloperidol, metoprolol, mirtazapine, perhexiline, quetiapine, risperidone, timolol, venlafaxine CYP2E1 Ethanol, halothane, methoxyflurane CYP3A4 Amiodarone, aprepitant, atorvastatin, carbamazepine, ciclosporin, erythromycin, felodipine, hydrocortisone, HIV protease inhibitors (e.g. saquinavir), simvastatin, tacrolimus, tyrosine kinase inhibitors (e.g. axitinib), verapamil, zolpidem Conjugation reactions These involve joining a suitable functional group present in the drug molecule with the polar group of an endogenous substance in the body (e.g. glucuronic acid, sulfate, acetyl- coenzyme A or glutathione). The conjugated drug molecule is generally more polar or more water-soluble, which enhances urinary excretion. Metabolism and excretion relationship  Table of conjugation reactions NZYME COFACTOR REACTION SUBSTRATE / METABOLITE UDP- UDP- Glucuronidatio Morphine/morphine-3-glucuronide glucuronosyltransferas glucuronic n Codeine/codeine-6-glucuronide es acid Sulfotransferases Sulfate Sulfation Salbutamol/salbutamol sulfate Paracetamol/paracetamol sulfate N-acetyltransferases Acetyl-CoA Acetylation Isoniazid/acetylisoniazid Clonazepam/7-acetamido- clonazepam Glutathione-S- Glutathione Glutathione Paracetamol/paracetamol– transferases conjugation glutathione conjugate Variability in drug metabolism genetics. environmental factors – for example, co- administered drugs, diet, alcohol, smoking. age and gender. disease states – for example, hepatic, cardiovascular. hormonal changes – for example, pregnancy. Drug interactions Metabolic drug interactions can occur when two or more chemicals(i.e. drugs or environmental chemicals) are present in the body at the same time. One chemical can alter the activity of the enzyme involved in eliminating the other chemical, (could be drug-drug, drug-herb or even drug-food). Enzymes can ne inhibited or induced (faster metabolism). A few examples of significant drug (inhibition- type metabolism related interactions) Inhibition of warfarin metabolism by amiodarone or fluconazole, increasing the risk of bleeding. Inhibition of azathioprine metabolism by allopurinol, increasing the risk of severe bone marrow toxicity and death. Inhibition of ciclosporin and tacrolimus metabolism by erythromycin, increasing the risk of nephrotoxicity and neurotoxicity. Inhibition of diazepam metabolism by cimetidine, prolonging central nervous system depression.  Disease states and hormonal factors In liver disease the effects are harder to predict because they In people with cardiac failure, depend on the disease type and liver perfusion and oxygenation severity, both of which can may be decreased, and this can influence drug metabolism. In reduce the activity of drug- general, in severe cirrhosis and metabolising enzymes. viral hepatitis the clearance of drugs metabolised by CYP is decreased. Hormonal factors During pregnancy, particularly third Metabolism of trimester increased caffeine may decline activity of CYP and during pregnancy. UGT enzymes. Carbamazepine and phenytoin dosage needs increasing to maintain therapeutic plasma levels. Excretion of drugs and drug metabolites Elimination refers to the irreversible loss of drug from the site of measurement by the processes of metabolism and excretion, but metabolites might remain. Excretion applies solely to the loss of unchanged drug or metabolites. The liver is the main organ of elimination. The kidneys are the main organ of excretion.  Hepatic and biliary excretion Lipophilic drugs diffuse freely across hepatocyte membranes. Presence of OATP, OCT,OAT and other uptake transporters facilitate the uptake of drugs that are cations, anions and other polar compounds. Once in the hepatocyte drugs are available for metabolism by the the CYP and UGT enzymes or for excretion into the bile by the efflux transporters (P-gp ,BCRP etc) located on the canalicular membrane. Metabolites formed within the hepatocyte may (1) diffuse, or (2) be transported (by MRP) across the apical membrane back into blood for subsequent excretion in urine, or (3) be transported into the bile (by the transporters present on the canalicular membrane), passed into the duodenum and excreted in faeces.  Drugs and drug metabolites that are excreted into Enterohepat bile become available for reabsorption once the bile ic recycling is released into the small intestine. In the small intestine the drug may be reabsorbed and returned to the liver via the portal vein, a process referred to as enterohepatic recycling. Since many drugs (e.g. atorvastatin, digoxin, ethinylestradiol, indometacin, morphine, rifampicin, kinase inhibitors and many antimicrobials) are excreted in bile to some extent, they are likely to undergo enterohepatic cycling to some degree. Glucuronide metabolites excreted into the bile can be hydrolysed by bacterial enzymes in the GIT to re-form the parent drug, which can subsequently undergo enterohepatic recycling.  Influences by the processes of glomerular filtration, tubular secretion and reabsorption. Glomerular filtration and tubular secretion facilitate transfer of drugs and metabolites from blood to urine, reabsorption counters these processes. Renal Free unbound drug and water-soluble metabolites are filtered by glomeruli excretion (glomerular filtration rate (GFR) is around 120ml/min). Protein-bound substances are not filtered. Drug transporters in the proximal tubule transfer drugs and metabolites that re organic acids and bases from the interstitial fluid into the tubule cell. Once in the urine lipophilic drugs can transfer back into the tubule cell and interstitial fluid (reabsorption).  Renal excretion cont… Most of the 120ml of water from filtered plasma at the glomerulus is reabsorbed during its passage through the renal tubule, only 1-2ml finally appears as urine. As water is reabsorbed a concentration gradient between drug in the tubular fluid and drug (unbound) in the blood is established. If drug is lipid soluble to pass through membrane will be reabsorbed into systemic circulation. If urine flow rate is high = (dilute urine) less concentration gradient and drug less reabsorption. Low urine flow rate= (concentrated urine) higher concentration gradrient and more reabsorption. Polar, water-soluble drugs such as acids, bases and glucuronide-metabolites are excreted in urine. Can block tubular secretion of drugs eg. probencid can block secretion of penicillin to prolong effects. Pulmonary excretion and other routes Gases and volatile drugs such as halothane are inhaled and excreted via lungs (exhalation). Excretion rate dependent on rate of respiration. Ethanol is highly soluble in blood (~ 1 part in 2000 is the gaseous state),pulmonary excretion forms the basis of the alcohol breath test. Excretion in sweat and saliva. Relatively unimportant because the process is slow compared to other forms and is minor proportion of total excretion. PK parameters and dosing regimens Rationale use of drugs based on assumptions that a particular concentration of drug will have desired therapeutic effect and that adverse effects will be minimal. Many drugs have a sufficient relationship between plasma drug concentration and clinical response to be designed to maintain the concentration within a therapeutic range. Therapeutic ranges are often selected on population-level data than from individuals. For some drugs dosing must be selected on the basis of individual characteristics (age, health status, kidney and liver function and the PK properties of the drug.  See below, single oral dose. Plasma Onset of action ~2hrs. concentration – Peak plasma concentration at 5hrs and a time profile 6hr duration of action. Plasma-time plot : Intravenous IV dosing not influenced dosing by absorption  Buried within the plasma drug concentration time profiles are the key parameters that help determine appropriate dosing regimens. Clearance, volume of distribution and half-life. Key PK Clearance and volume of distribution are parameters determined by both the patient and the drug. Plasma half-life is a composite parameter related directly to the volume of distribution and inversely to drug clearance. Area under the plasma concentration versus time curve (AUC) Describes drug concentration in the systemic circulation as a function of time post-dose. Can be used to calculate both the clearance of drug after IV admin and its bioavailability (comparing AUC values of IV and po admin of same drug.  Drug clearance Ability of organ or the body to eliminate a drug. Clearances by each organ are additive. CLSystemic=CLRenal+CLHepatic+CLOther  Hepatic clearance CLH= Hepatic extraction ratio EH multiplied by liver blood flow QH i.e. CLH=EH X QH Low hepatic clearance drugs are Hepatic considered capacity-limited, the capacity of the liver enzymes is the clearance rate-limiting factor determining extraction. High hepatic clearance is where delivery of the drug to liver is the limiting factor determining extraction.  LOW CLEARANCE INTERMEDIATE HIGH CLEARANCE CLEARANCE Hepatic Carbamazepine Caffeine Lidocaine (lignocaine) clearance Diazepam Fluoxetine Morphine examples Ibuprofen Midazolam Propofol Phenytoin Omeprazole Propranolol Warfarin Paracetamol Zidovudine Renal clearance Only unbound drug undergoes glomerular filtration. Renally excreted drugs may require dose adjustment in renal impairment. Dose adjustment of renally excreted drugs of narrow therapeutic index is of critical important with mandatory therapeutic drug monitoring for some drugs irrespective of baseline renal function (e.g. gentamicin). Calculated creatinine clearance calculated by the Cockcoft-Gault formula can be used for estimating renal function where there is a need for drug dosage adjustment in people with renal impairment. (however see latest NZF recommendations) The Cockcroft–Gault formula is: Creatinine clearance (CrCl)(mL/min)=(140−age)×(lean body weight in kg)×(0.85 for females)÷SCr (micromol/L)×0.815  Continued drug administration leads to a situation where rate of drug going in equals Clearance rate of drug going out referred to as steady and steady state (approx. 3-5 plasma half-lives) Maintenance dose can be calculated from state clearance and steady state plasma drug concentration. Volume of distribution Abstract term not referring to a real volume. Indicates accumulation of drugs in extravascular compartments (fat, muscle). Helps determine half life of the drug and is used to calculate loading doses where you need to fill up the volume of distribution quickly for rapid therapeutic effect, eg digoxin and IV vancomycin.  Commonly used to describe a person's exposure to the drug. Major determinant of duration of action after a single oral dose. For repeated dosing, if drug is administered every half life (i.e. dosing interval same as half-life),then the concentration will fall by one half between doses. Half-life Influenced by distribution and clearance, e.g. in heart failure a decreased volume of distribution and decreased liver blood flow can mean changes in drug half-life, or those with kidney or liver disease. In general, the time taken to reach steady- state drug plasma concentrations in chronic dosing is three to five half-lives. Saturable metabolism Previous discussions of half-life assume a constant proportion of drug is eliminated in unit time (A). First order kinetics When metabolism is saturated, the rate of elimination does not increase in proportion of the dose and half-life and clearance increased (B). Zero order kinetics (e.g. phenytoin)  Common PK parameters /concepts CONCEPT SYMBOL EQUATION PARAMETERS AND COMMON UNITS Bioavailability F F = f g× f H f g = fraction of oral dose absorbed f H = fraction of drug escaping hepatic extraction Systemic clearance CL S CL H + CL R + CL Other CL S = L/h Hepatic clearance CL H CL H = E H × Q H CL H = L/h or mL/min Q H = liver blood flow = 90 L/h Hepatic extraction ratio E H E H = CL H ÷ Q H Ratio Renal clearance by glomerular CL GF CL GF = f u × GFR f u = fraction of drug unbound in plasma filtration GFR = glomerular filtration rate Maintenance dose rate (IV dose) DR DR = CL × C SS DR = mg/h C SS = mg/L Concentration at steady state (IV C SS C SS = DR ÷ CL CL = L/h or mL/min dose) Concentration at steady state (oral C SS C SS = F × DR ÷ CL F = bioavailability = 0–1 dose) Loading dose LD LD = V D × C V D = volume of distribution (L) C = target plasma concentration (mg/L) Half-life t 1/2 t 1/2 = 0.693 × V D ÷ t 1/2 units can be minutes or hours or days or Questions