Pharmacology: Drug Elimination and Hepatic Clearance

Drug Elimination and Hepatic Clearance

• Drug elimination is the decline in peak plasma concentrations due to metabolism and renal excretion.
• The primary site of metabolism is the liver. Other sites include the lung, skin, gastrointestinal mucosa, distal ileum, large intestine, and kidneys.
• Factors like renal and hepatic disease, and drug-drug interactions can affect drug elimination.
• Variability in elimination half-lives exists for highly metabolized drugs, like phenytoin, theophylline, and lidocaine, due to genetic and environmental factors. Renal excretion variability is less for primarily renally excreted drugs.
• Renal drug excretion depends on glomerular filtration rate (GFR) and kidney blood flow.
• Hepatic clearance is the volume of blood that perfuses the liver, cleared of drug per unit of time.
• First-order elimination means the rate of elimination is constant, with the sum of metabolism (km) and excretion (ke) rate constants. (k = km + ke).
• Excretion rate constant (ke) is easily determined for drugs primarily removed by the kidneys.
• The fraction (fe) of drug excreted unchanged in urine, and (1 - fe) fraction of drug metabolized, can be measured.
• If renal pathways are impaired, hepatic metabolism becomes the primary elimination route; conversely, liver function decline leads to increased renal elimination.
• Total body clearance (Cl+) refers to the sum of all clearances in the body, which represents the volume of blood or plasma from which a drug is completely removed per unit time.
• Total body (systemic) clearance is used to measure how effectively the body eliminates drugs.

Enzyme Kinetics

• The rate of metabolism is a first-order process, where plasma drug concentration is relatively high, and all enzyme molecules become complexed with drug.
• The reaction rate becomes maximal (Vmax), when the substrate concentration (drug) is high and the rate proceeds at zero-order.
• The Michaelis constant (KM) corresponds to the drug concentration when the reaction velocity is at half Vmax.
• The Michaelis-Menten equation describes drug metabolism rate processes.
• It assumes the drug and enzyme concentrations are both constant and an energetically favored drug-enzyme intermediate is initially formed.
• When all the enzymes are saturated, rate is dependent on availability of enzymes, and then the reaction proceeds at zero order maximum velocity.

Biotransformation

• Transformation of drug to metabolites, is a kinetic process, dependent on the drug's concentration and the corresponding enzyme saturation.
• This process includes oxidation, reduction, hydrolysis, and conjugation reactions.
• Drugs' metabolic rate and drug elimination half-life are correlated.
• Key enzymes involved in biotransformation include mixed-function oxidases (MFOS).
• Enzymes involved, like CYP450, are structural and an electron-transport system that requires: NADPH (NADPH2), Molecular oxygen, and CYP450/NADPH-CYP450 reductase.

Types of Enzyme Inhibition

• Competitive: Inhibitor and drug compete for same active site on the enzyme (similar chemical structures).
• Noncompetitive: Inhibitor binds to a different site on the enzyme (allosteric site).
• Uncompetitive: Inhibitor interacts with enzyme-substrate complex.

Pharmacokinetics

• Pravastatin, has variable bioavailability (50-60% for AUC and average of 34%)
• Extensive first pass extraction in the liver (extraction ratio 0.66).
• Cyclosporine significantly affects pravastatin by inhibiting hepatic transporters.
• Drug-drug interactions should be monitored.

Drug-Drug interactions

• Affecting drug metabolism.
• Enzyme induction: increase in enzyme activity (e.g., Rifampin, Phenobarbital, Carbamazepine).
• Enzyme inhibition: decrease in enzyme activity (e.g., Ketoconazole and Ranitidine).
• Drug metabolism inhibition and induction is a known pharmacokinetic factor

Transporter-Based Interactions

• These can include inhibitors or inducers of transporters.
• Multidrug resistance protein, MDR1/P-gp, is a major transporter for digoxin.
• P-gp inhibitors (e.g., Ritonavir and quinidine) can increase digoxin levels.

First-Pass Effect and Liver Extraction Ratio (ER)

• A phenomenon whereby a drug absorbed from the GI tract is metabolized in the liver before systemic circulation. ER is associated with the fraction of drug removed from the blood by the liver.
• For high ER drugs, a high percentage of the circulating drug is removed by the liver before reaching systemic circulation, leading to lower bioavailability. Conversely, low ER drugs are less affected by first-pass effect due to lower hepatic clearance.
• Changes in liver blood flow affect hepatic clearance, which in turn can impact clinical outcome or dosing changes, as a result.

Species Differences

• Genetic differences can significantly affect hepatic biotransformation enzymes.
• This can lead to variations in drug metabolism rates between species (e.g., humans, rats, dogs).
• Environmental factors can also contribute.

Specific Examples

• Drugs like propranolol, morphine, ibuprofen, digoxin, theophylline, phenytoin, and others have been discussed for their hepatic clearance mechanisms.
• Examples of enzyme inhibition and induction, and substrate/drug interactions, to affect metabolism have also been described.

Biliary Excretion

• Drugs or their metabolites are secreted into bile and excreted through feces.
• This process involves an active secretion process into the liver.
• The rate of drug elimination is measured by monitoring compounds secreted into the Gl perfusate.
• Factors like biliary secretion are relevant for appropriate dosing and clinical monitoring.

Liver Anatomy and Physiology

• The liver is a major organ related to drug metabolism.
• It has a complex structure with a highly vascularized network, which is crucial for its metabolic function.