Lecture 4 Drug Metabolism

Pharmacology Lecture 4 Drug Metabolism

1) Highlight Importance of Biotransformation. Biotransformation is the modification of drugs by enzymes that are present for endogenous substrates to decrease lipid solubility and increase ionization, thus promoting excretion. Biotransformation is important because it: a) Determines therapeutic half-life b) May produce “Active Metabolites” c) Is the site of Drug-Drug Interaction d) Produces Toxic Metabolites or Intermediates 2) Describe Major Biotransformation Pathways. Phase I Biotransformation: usually CYP450 exposes or adds functional groups to a variety of substrates through various reactions like oxidation and hydrolysis. a) Cytochrome P-450 is a family of enzymes found primarily in the liver with 17 subgroups classified by their biochemical characteristics.

b) Amides and esters can be hydrolyzed by esterases and amidases that add water across the bond thus exposing functional groups. Phase II Biotransformation: Occurs through conjugation of an endogenous group and a drug, which increases water solubility, ionization, and ultimately excretion. a) The following table lists Major Conjugation Reactions. Conjugation Conjugate Chem Group

Glucuronidation Acidic Sugar (UDPGA) -OH, -COOH, -NH2, -SH

Sulfation Sulfate -OH, -NH2 + Methylation CH3 -OH, -NH2 - Acetylation CH3COO -NH2 Amino Acid Amino Acid -COOH Glutathione GSH Electrophiles 3) Discuss “Chemical” Factors that Affect Biotransformation. a) Enzyme induction: increased rate of biotransformation or increased number of enzymes resulting in decreased half-life. Some inducing agents include: Classification Drug Anesthetic Gas Halothane Hypnotic/Sedative Barbituates, Chloral Hydrate, Ethanol Anticonvulsants Diphenylhydantion Anti-Inflammatory Phenylbutazone, Aminopyrine Hypoglycemics Tolbutamide Antihistamines Chlorclyclizine The effects of induction may persist for weeks. Herbal supplements may also have inducing properties like St. John’s Wort. b) Enzyme inhibition: decreased rate of biotransformation and drug-drug interactions can cause an increased half-life and exacerbated pharmacological effect. Drug-Drug interactions result from competition for the same enzyme(s). They should be considered with polypharmacy by consulting the PDR, drug inserts, and reports. Prevention is difficult but several strategies exist: patient profiling of phenotypes, pre-screening of drugs for isozyme interaction, and consulting drug interaction tables that take inhibitors, inducers, and genetics into account. c) Dietary inhibition: citrus juices, primarily grapefruit juice (bergamottin), inhibit CYP3A thus increasing the half-life of drugs it metabolizes. d) First pass biotransformation: although discussed previously it involves the effectiveness of liver enzymes to metabolize a drug before it reaches the blood. 4) Evaluate Biological Factors that Influence Biotransformation. a) Genetic Variation – fairly consistent, but variation can be up to three times (or higher) the norm. This is due to the isoforms present, their activity and quantity. b) Sex – some small effects exist with selective drugs including ethanol. Chlordiazepoxide and diazepam have longer half lives in women than men. c) Development of Drug Metabolism – may be deficient at birth (Glucuronyl Transferases). Phase I is less active but reaches adult levels by 1-3 months. d) Age – effects include: ↓absorption, ↓biotransformation (↓liver size, ↓hepatic blood flow, ↓activity), ↓distribution, and ↓excretion. e) Disease – liver disease reduces biotransformation rate. 5) Present Concept of Detoxication vs Bioactivation. Detoxication is the metabolism of xenobiotics to innocuous metabolites that can be readily excreted. Bioactivation is the metabolism of xenobiotics to active metabolites that exert some biological effect on the organism. Acetaminophen demonstrates these concepts where detoxication occurs through the formation of sulfate and glucuronide conjugates while bioactivation occurs through P450 resulting in a reactive metabolite, which can be detoxified depending on the availability of GSH for conjugation. When GSH is depleted liver necrosis results.