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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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 )

12. 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