By: Dr. Roshini Murugupillai Pharmacokinetics II By: Dr. Roshini Murugupillai

Biotransformation/ Metabolism Biotransformation is the chemical alteration of the drug in the body Primary sites for drug metabolism: Liver Kidney Intestine Lungs Plasma Biotransformation processes change drugs in two major ways: By reducing lipid solubility By altering biological activity

Biotransformation of drugs may leads to the following: Inactivation - conversion of pharmacologically active substance in to an inactive substance Active metabolite from an active drug - conversion of one pharmacologically active to another active substance e.g. Digitoxin - Digoxin Activation of inactive drug - conversion of pharmacologically inactive substance (prodrug) to an active substance e.g. Levodopa - Dopamine

Classification of biotransformation reactions: Non-synthetic/Phase I reactions Metabolite may be active or inactive Synthetic/conjugation/Phase II reactions Metabolite is mostly inactive Oxidation Reduction Hydrolysis Cyclization Decyclization

Synthetic/Phase II reactions These involve conjugation of the drug or its phase I metabolite with an endogenous substrate to form a polar highly ionized organic acid which is easily excreted in urine or bile These synthetic reactions have high energy requirement Glucuronide conjugation E.g. aspirin, metronidazole Acetylation E.g. sulfonamides, isoniazid Methylation E.g. adrenaline Glutathione conjugation E.g. paracetamol

Most of the drugs are metabolized by more than one pathways, simultaneously or sequentially Majority of the drugs are acted upon by nonspecific enzymes i.e. the same enzyme can metabolize many drugs Only few are drugs are metabolized by a specific enzyme e.g. Allopurinol by Xanthine oxidase Metabolism Excretion Drug Phase I Metabolite Phase II

The drug metabolizing enzymes are of two types: microsomal enzymes non-microsomal enzymes Microsomal enzymes These are located on the sER primarily in liver, also in kidney, intestinal mucosa, lungs E.g. monooxigenases, cytochrome P450, glucuronyl transferase They catalyze most of the oxidations, reductions, hydrolysis & glucuronide conjugation Microsomal enzymes are inducible by drugs, diet & other substances

Non-microsomal enzymes These are present in the cytoplasm and mitochondria of hepatic cells & other tissues, plasma E.g. esterases, amidases, conjugases They catalyze, some oxidations & reductions, many hydrolytic reactions and all conjugations except glucuronidation These enzymes are not inducible Many enzymes shows genetic polymorphism e.g. acetyl transferase, pseudocholinesterase Both microsomal & non-microsomal enzymes are deficient in New borns. Hence, they are more susceptible to many drugs

Inhibition of drug metabolism Hofmann elimination This refers to inactivation of the drug in the body fluids by spontaneous molecular rearrangement without any enzyme E.g. Atracurium Inhibition of drug metabolism Some drugs may competitively inhibit the metabolism of another drug/s if it utilizes the same enzyme However, such inhibitions are not very common E.g. chloramphenecol, omeprazole, ciprofloxacin

Microsomal enzyme induction Many drugs, insecticides (DDT) increase the synthesis of microsomal enzyme protein ( cytochrome P450, glucuronyl tranferase) As a result, the rate of the metabolism of inducing drug itself &/or other drugs are increased Different inducers are relatively selective to a certain cytochrome P450 enzyme families Some isoenzymes are utilized by larger number of drugs. If these isoenzymes are induced, it will affect the metabolism of many drugs e.g. Phenobarbitone affects the metabolism of many drugs

Consequences of microsomal enzyme induction Decreased plasma concentration/duration of action of drug e.g. failure of contraception with OCP Increased intensity of action of drugs that are activated by metabolism resulting in toxicity Tolerance –due to auto induction, large dose will be required Some endogenous substrates are also metabolized faster ( steroids, bilirubin) Intermittent use of an inducer may interfere with dose adjustment of another drug prescribed on a regular basis (antihypertensives, oral hypoglycemics, oral anticoagulants, antiepileptics )

First pass metabolism Metabolism of a drug during its passage from the site of absorption into the systemic circulation This differs for different drugs & an important determinant of bioavailability All orally administered drugs are exposed to drug metabolizing enzymes in intestinal mucosa & liver Attributes of drugs with high first pass metabolism: Oral dose is considerably higher than the parenteral/ sublingual dose Marked individual variation in the oral dose Oral bioavailability is apparently increased in patients with liver disease Oral bioavailability of a drug is increased if another drug competing with it for metabolizing enzymes is given simultaneously