Drug metabolism

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  Biotransformation of drugs is essential to facilitate their excretion. For
example, lipid-soluble drugs are not easily excreted from the kidney as these are
reabsorbed through renal tubules into the blood stream. Drug metabolism aims to
convert the drug into a water-soluble form easily excreted from the body.
  There are two main types of drug biotransformation reactions, namely phase I
and phase II reactions.
Phase I reactions:
  These are non-synthetic reactions  performed mainly by liver microsomal
enzymes called cytochrome P-450 (CYP-450) enzymes. There are many subfamilies,
each responsible for the metabolism of certain drug classes, including CYP1A2,
CYP2E1, CYP3A4, ..etc. Phase I reactions include oxidation, reduction, hydrolysis,
oxidative deamination, sulfoxidation, O-delakylation, N-dealkylation  and  aromatic
hydroxylation.
  Induction and inhibition of  liver microsomal enzymes affect drug
pharmacokinetics massively. For example, induction of liver microsomal enzymes
reduces the action of potent drugs administered in low doses like anticoagulants and
contraceptives.  Additionally, drugs converted to toxic  forms by liver microsomal
enzymes like paracetamol, isoniazid and D-galactosamine, show increased toxicity by
microsomal enzyme induction.  The reverse is true for liver microsomal enzyme
inhibition.
  Inducers of liver microsomal enzymes include:
  Acute alcohol ingestion.
  Drugs like phenobarbital (increases its own metabolism leading to tolerance)
and phenytoin (increases codeine metabolism).
  Diseases like diabetes mellitus.
  Fasting.
  Hormones like insulin (stimulates barbiturate metabolism).
Alternatively, inhibitors of liver microsomal enzymes include:
  Chronic alcohol ingestion (inhibits phenobarbital metabolim).
  Drugs like cimetidine  (broad-spectrum inhibitor), dicoumarol  (inhibits
phenytoin metabolism) and phenylbutazone (inhibits tolbutamide metabolism).
  Toxic doses of radiation.
  Diseases like hypothyroidism and neoplastic diseases.
  Hormones like estrogens and progestins (inhibit mepiridine metabolism).
Effect of biotransformation reactions on drug activity and toxicity:
1- A drug may be converted from an active form to an equally active form (e.g.
hydrolysis of aspirin to salicylic acid).
2- A drug may be converted from an active form to an inactive form (e.g.
hydrolysis of acetylcholine to choline and acetic acid).
3- A drug may be converted from an active form to a toxic form (e.g. oxidation of
methanol to formaldehyde).
4- A drug may be converted from an active form to metabolites with different
activities (e.g. phenylbutazone is oxidized to two metabolites; one anti-
rheumatic and another uricosuric).
5- A drug may be converted from an inactive form to an active form (e.g.
reduction of chloral hydrate to trichloroethanol).
6- A toxicant may be converted from an inactive form to a toxic form (e.g.
oxidation of parathion to toxic metabolite).
Phase II reactions:
  These are synthetic or conjugation reactions. These always terminate in a safe
product that is water-soluble and easily excreatble. Drugs are subjected to phase II
reactions directly or after phase I reactions (most cases). In few cases, drugs may be
subjected to phase I after phase II reactions.
Phase II reactions involve conjugation with water-soluble endogenous
molecules as shown in the following table:
 

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