Drug metabolism

Phase I reactions: Reactions that convert the drug to a more polar (water-soluble) or more reactive product by unmasking or inserting a polar functional group such a -OH, -SH, or -NH2. This includes oxidation (especially the cytochrome P450 group of enzymes, a.k.a mixed function oxidases), reduction, deamination, and hydrolysis.

Hydrolysis of esters: Succinylcholine is an ester that is rapidly metabolized (in 5 min) by plasma cholinesterase ("pseudocholinesterase" or butyrylcholinesterase). 1:2500 person has an abnormal form of this enzyme that slowly metabolizes succinylcholine and similar esters. In such individuals, the neuromuscular paralysis produced by a single dose of succinylcholine may last many hours.

Phase II reactions: Reactions that increase water solubility by involving addition (conjugation) of subgroups -OH, -NH2, and -SH functions on the drug molecule. The subgroups that are added include glucuronate, acetate, glutathione, glycine, sulfate, and methyl groups. Most of these groups are relatively polar and make the product less lipid-soluble than the original drug molecule.

Acetylation of amines: INH and some other amines such as procainamide are inactivated by N-acetylation. Individuals who are deficient in acetylation capacity, termed slow acetylators may have prolonged or toxic responses to normal doses of these drugs. It is inherited as an autosomal recessive gene. They constitute 50% of white and AA persons in USA, and a small fraction of Asian and Inuit populations. Also, there is some evidence linking slow acetylation to increased susceptibility to drug-induced lupus erythematosus.

Enzyme induction: Induction results from increased synthesis of cytochrome P450-dependent drug-oxidising enzymes in the liver. Many isozymes of the P450 family exist, and inducers selectively increase subgroups of isozymes. Several days are required to reach maximum induction; a similar amount of time is required to regress after withdrawal of the inducer. Some drugs induce their own metabolism.

Inhibitors of intestinal P-glycoprotein: P-gp is identified as an important modulator of intestinal drug transport and usually functions to expel drugs from the intestinal mucosa into the lumen. Other members of P-gp family are found in the blood-brain barrier and in multiply drug-resistant cancer cells. Drugs that inhibit P-gp increase their bioavailability and may reach toxic concentrations even if given in non-toxic doses. E.g: verapamil, grapefruit juice. Important drugs that are normally expelled by P-gp (and which are therefore potentially more toxic when given with a P-gp inhibitor) include digoxin, cyclosporine, and saquinavir.

Acetaminophen is conjugated into harmless glucuronide and sulfate metabolites when taken in normal doses. If a large dose is taken, however, the metabolic pathway is overwhelmed, and a P450-dependent system converts some of the drug to a reactive intermediate (N-acetyl-p-benzoquinoneimine). This intermediate is conjugated with glutathione to a third harmless product. If glutathione stores are inadequate, the reactive intermediate is hepatotoxic and results in hepatic cell necrosis. Prompt administration of sulfhydryl donors (acetylcysteine) may be life-saving after an overdose. In patients with severe liver disease, stores of glucuronide sulfate, and glutathione may be depleted, making the patient more susceptible to hepatic toxicity with near-normal doses of acetaminophen. Ethanol exhausts glutathione stores, and may increased APAP toxicity. Similarly phenobarbital and phenytoin, may increase APAP toxicity because they increase phase I metabolism more than phase II metabolism, thus resulting in increased production of the reactive metabolite.