METABOLISM OF DRUG
- Also referred to as “Biotransformation”.
- Primary site: Liver.
Classification:
- Non-synthetic/phase I/functionalization reactions:
- Functional group is generated or exposed-metabolite may be active or inactive.
- Synthetic/phase II reactions/conjugation:
- Metabolite is mostly inactive.
- Exceptions e.g. Glucuronide conjugate of morphine & sulfate conjugate of minoxidil are active.
Steps for biotransformation:
- May occur with help of microsomal or non-microsomal enzymes.
- Microsomal enzymes present in smooth endoplasmic reticulum.
- Eg of microsomal enzymes: Cytochrome P-450, UGTs.
- Results in increased metabolic rate of inducing drug itself or other drugs.
- Inducers are relatively selective for certain isoenzyme families.
Microsomal enzyme induction:
- Drugs induce microsomal enzymes & hence, drug metabolism induced.
- Eg:
- CYP3A isoenzyme inducer:
- Anticonvulsants (phenobarbitone, phenytoin, carbamazepine), rifampin, glucocorticoids.
- CYP2B1 inducer:
- Phenobarbitone.
- CYP2D6 inducer:
- Rifampin.
- CYP2E1 inducer:
- Isoniazid & chronic alcohol consumption.
- CYP1A inducer:
- Polycyclic hydrocarbons like 3-methylcholanthrene and benzopyrene found in cigarette smoke, charcoal, broiled meat, omeprazole & industrial pollutants.
- Other important enzyme inducers:
- Phenylbutazone, griseofulvin, DDT.
Drug-to-drug interaction by enzyme induction:
1. Drugs enhancing drug metabolism in humans:
| Inducing drug | Drug with enhanced metabolism |
| Benzo[a]pyrene | Theophylline |
| Chlorcyclizine | Steroid hormones |
| Ethchlorvynol | Warfarin |
| Glutethimide | Antipyrine, glutethimide, warfarin |
| Griseofulvin | Warfarin |
| Barbiturates
(except secobarbital) |
Barbiturates, chloramphenicol, chlorpromazine, cortisol, coumarin anticoagulants, desmethylimipramine, digitoxin, doxorubicin, estradiol, phenylbutazone, phenytoin, quinine, testosterone |
| Phenylbutazone | Aminopyrine, cortisol, digitoxin |
| Phenytoin | Cortisol, dexamethasone, digitoxin, theophylline |
| Rifampin | Coumarin anticoagulants, digitoxin, glucocorticoids, methadone, metoprolol, oral contraceptives, prednisone, propranolol, quinidine |
2. Drug inhibiting drug metabolism in humans:
| Inhibitor | Drug whose metabolism is inhibited |
| Allopurinol, Isoniazid
Chloramphenicol |
Antipyrine, dicumarol, probenecid, tolbutamide |
| Cimetidine | Chlordiazepoxide, diazepam, warfarin, others |
| Dicumarol | Phenytoin |
| Diethylpentenamide | Diethylpentenamide |
| Disulfiram | Antipyrine, ethanol, phenytoin, warfarin |
| Ethanol | Chlordiazepoxide, diazepam, methanol |
| Grapefruit juice | Alprazolam, atorvastatin,cisapride, cyclosporine, midazotam,Triazolam |
| Ketoconazole | Cyclosporine, astemizole, terfenadine |
| Nortriptyline, Oral contraceptives | Antipyrine |
| Phenylbutazone | Phenytoin, tolbutamide |
| Secobarbital | Secobarbital |
| Troleandomycin | Theophylline, methylprednisolone |
Exam Important
- Non-synthetic is also referred to as “phase I/functionalization reactions”.
- Synthetic is also referred to as “phase II/conjugation reactions”.
- Glucuronide conjugate of morphine & sulfate conjugate of minoxidil is active.
Don’t Forget to Solve all the previous Year Question asked on METABOLISM OF DRUG
