Pharmacokinetics: Drug Metabolism and Excretion

• This lecture covers pharmacokinetics, focusing on drug metabolism and excretion.
• By the end of this lecture, students should be able to list major phase 1 & 2 metabolic reactions.
• They should also be able to explain genetic variability, list enzyme inducing/inhibiting drugs and predict dosage adjustments with enzyme inhibitors/inducers.
• They also need to be able to predict the effect of renal diseases on drug pharmacokinetics.

Drug Metabolism (Biotransformation)

• Primarily occurs in the liver, but also in intestinal lumen/wall, lung, plasma, skin, and kidney.
• The main goal is to convert drugs into more polar (ionized) metabolites for easier excretion.

Results/Consequences of Drug Metabolism

• Abolishing activity (most drugs): Active Drug becomes Inactive Drug.
• Prodrugs are converted into active drugs: Prodrug -> Active Drug in Liver -> Inactive Drug.
  • Examples: Enalapril to enalaprilat, Prednisone to prednisolone.
• Active drugs are converted to more active forms, which then become inactive.
  • Examples: Codeine to morphine, Diazepam to Nor diazepam.
• Some drugs are converted into toxic metabolites.
  • For example, Paracetamol becomes a toxic epoxide, which is then conjugated with glutathione.

Types of Biotransformation Reactions

• Phase I: Converts drugs to inactive polar forms or still active non-polar forms.
• Phase II: Converts remaining active non-polar forms to 99% inactive polar forms.
• Reversed Phase: Isoniazide (INH)

Phase I vs Phase II Reactions

• Phase I (Non-Synthetic):
  • Involves oxidation, reduction, or hydrolysis. -Unmasks a polar group, converting the drug to an ionized metabolite for excretion.
  • Example enzyme system: cytochrome P450.
• Phase II (Synthetic):
  • Conjugates an endogenous substrate (e.g., glucuronic acid, glycine, glutathione, sulfate) with the drug or its metabolite.
  • Forms non-toxic, highly polar, inactive, rapidly eliminated conjugates.
  • Example enzyme: Glucuronyl transferase.

Metabolizing Enzyme Systems

• Microsomal Enzymes:
  • Cytochrome P450 (Phase 1)
  • Glucuronyl transferase (Phase 2): These are liable for induction and inhibition
• Non-Microsomal Enzymes:
  • Plasma Ach esterase
  • Cytoplasmic xanthine oxidase The cytochrome P450 system has genetic variability.

Factors Affecting Biotransformation

• Physiological changes due to age and sex. Metabolism is generally higher in men (hormonal).
• Pathological factors such as liver cell failure.
• Pharmacogenetic variations in metabolizing enzymes, considering types and amounts.
• Enzyme induction and enzyme inhibition.

Enzyme Induction

• Certain drugs stimulate the activity and amount of microsomal enzyme systems responsible for their own metabolism and that of other drugs administered together.
• This process is reversible, occurring over a few days and passing off over 2-3 weeks after the inducer is withdrawn.
• Examples of enzyme inducers include:
  • Phenobarbitone
  • Phenytoin
  • Carbamazepine
  • Rifampicin
  • Nicotine
• Clinical Value:
  • Increases its own metabolism, leading to tolerance (e.g., phenobarbitone).
  • Increases the metabolism of other drugs, reducing their therapeutic effect.
    • Example drug interactions: Rifampicin reduces the effectiveness of oral contraceptives, and increases risk of pregnancy.
    • Phenytoin increases metabolism of vitamin D -> osteomalacia.
    • Rifampicin increases metabolism of warfarin, reducing anticoagulation.
  • Can be overcome by increasing the dose of other drugs.
  • Can increase metabolism of endogenous substrates, like phenobarbitone enhancing bilirubin elimination in neonatal jaundice.

Enzyme Inhibition

• Certain drugs inhibit microsomal enzyme systems, decreasing their activity and potentially causing toxicity of other drugs.
• It is reversible: effects occur over a few days and disappear over 2-3 weeks after stopping the inhibitor.
• Examples of enzyme inhibitors include:
  • Chloramphenicol
  • Erythromycin
  • Ciprofloxacin
  • Valproate

Clinical Value of Enzyme Inhibition

• Decreased metabolism of drugs given simultaneously leads to increased levels and risk of toxicity.
  • Drug interactions: Erythromycin inhibits theophylline metabolism, and ciprofloxacin inhibits warfarin metabolism -> bleeding.
  • Can be overcome by decreasing the dose of other drugs.

Drug Excretion

• The kidney is the most important route.
• Other excretion sites include:
  • Lungs (e.g., volatile anesthetics)
  • Saliva (e.g., iodides)
  • Bile (e.g., rifampicin)
  • Milk (important for lactating mothers)

Renal Elimination of a Drug

• Filtration: Affected by glomerular filtration rate (GFR), plasma protein binding (prevents filtration), and lipophilicity (inhibits excretion).
• Active Tubular Secretion: Secretes organic acids.
• Reabsorption: Occurs if the unionized form is lipid soluble; depends on pH of the medium and pKa of the drug.

Interactions at Site of Excretion

• Alkalization of urine (using NaHCO3) increases ionization of acidic drugs (e.g., aspirin), decreasing tubular reabsorption and increasing excretion, which is useful in cases of toxicity.
• Acidification of urine (using Vitamin C) increases ionization of basic drugs (e.g., amphetamines), decreasing tubular reabsorption and increasing excretion, which is useful in cases of toxicity.
• Active Tubular Secretion: Probenecid competes with penicillin for renal tubular excretion, inhibiting penicillin excretion and prolonging its action.
  • Hyperuricemia is associated with diuretic (thiazide) administration.

Effects of Drug Lipophilicity on Pharmacokinetic Parameters

• Increased lipophilicity increases drug absorption.
• Increased lipophilicity increases the volume of distribution (Vd), as lipophilic drugs can penetrate into most tissues.
• Lipophilic drugs can cross the central nervous system (CNS).
• Increased lipophilicity increases hepatic elimination (lipophilic drugs can enter hepatocytes).
• Increased lipophilicity decreases renal excretion due to increased tubular re-absorption.
• Drug elimination does not always end the therapeutic effect. Irreversible inhibitors (e.g., aspirin, PPIs, MAOIs) will have a therapeutic effect long after the drug is eliminated.