Biotransformation

BIOTRANSFORMATION

(Metabolism)

Biotransformation means chemical alteration of the drug in the body. It is needed to render nonpolar (lipid-soluble) compounds polar (lipid-insoluble) so that they are not reabsorbed in the renal tubules and are excreted. Most hydrophilic drugs, e.g. streptomycin, neostigmine, pancuronium, etc. are little biotransformed and are largely excreted unchanged. Mechanisms which metabolize drugs (essentially foreign substances) have developed to protect the body from ingested toxins.

The primary site for drug metabolism is liver; others are—kidney, intestine, lungs and plasma. Biotransformation of drugs may lead to the following.

i)                   Inactivation

Most drugs and their active metabolites are rendered inactive or less active, e.g. ibuprofen, paracetamol, lidocaine, chloramphenicol, propranolol and its active metabolite 4hydroxypropranolol.

    ii)  Active metabolite from an active drug

Many drugs have been found to be partially converted to one or more active metabolite; the effects observed are the sumtotal of that due to the parent drug and its active metabolite(s).

ii)                Activation of inactive drug

Few drugs are inactive as such and need conversion in the body to one or more active metabolites. Such a drug is called a prodrug (See box). The prodrug may offer advantages over the active form in being more stable, having better bioavailability or other desirable pharmacokinetic properties or less side effects and toxicity. Some prodrugs are activated selectively at the site of action.

Active Drug            Active Metabolite

Chloral hydrate — Trichloroethanol

Morphine    — Morphine6glucuronide

Cefotaxime — Desacetyl cefotaxime

Allopurinol — Alloxanthine

Procainamide        — Nacetyl procainamide

Primidone   — Phenobarbitone,

phenylethylmalonamide

Diazepam   — Desmethyldiazepam,

                                         oxazepam

Digitoxin    — Digoxin

Imipramine — Desipramine

Amitriptyline        — Nortriptyline

Codeine      — Morphine

Spironolactone  — Canrenone

Losartan      — E 3174

Biotransformation reactions can be classified into:

a) Nonsynthetic/Phase I/Functionalization reactions: a functional group is generated or exposed—metabolite may be active or inactive.

b) Synthetic/Conjugation/ Phase II reactions: metabolite is mostly inactive; except few drugs, e.g. glucuronide conjugate of morphine and sulfate conjugate of minoxidil are active.

Prodrug           Active form

Prodrug          Active Form

Levodopa     — Dopamine

Enalapril      — Enalaprilat

αMethyldopa — αmethylnorepinephrine

Dipivefrine    — Epinephrine

Sulindac        — Sulfide metabolite

Proguanil    — Cycloguanil

Prednisone  — Prednisolone

Bacampicillin — Ampicillin

Sulfasalazine — 5Aminosalicylic acid

Cyclophosphamide                   — Aldophosphamide, phosphoramide                              mustard, acrolein

Fluorouracil — Fluorouridine monophosphate

Mercaptopurine — Methylmercaptopurine ribonucleotide

Acyclovir    — Acyclovir triphosphate