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Pharmacologically Active Metabolites of Drugs and Other Foreign Compounds

Clinical, Pharmacological, Therapeutic and Toxicological Considerations

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Summary

Drugs and other foreign compounds administered to man may be biotransformed into metabolites that are pharmacologically active. These metabolites can either be beneficial at the right concentrations in the body or pharmacodynamically toxic, and in some instances they can be responsible for the pharmacological activity seen after parent drug administration. When urinary excretion is the major pathway of elimination of the active metabolite, it will accumulate in patients with renal failure given the parent drug. If the metabolite has the same pattern of pharmacological response as the parent drug, the patient will appear to have an enhanced intensity of effect. If the metabolite has a pattern of pharmacological activity different from that of the parent drug, the effects observed may differ qualitatively as well as quantitatively from what was expected. A few examples of this have been demonstrated in man: (a) the therapeutic (abolition of premature ventricular contractions and prevention of paroxysmal atrial tachycardia) and toxic effects of procainamide in some cardiac patients with poor renal function are associated with high levels of N-acetylprocainamide; (b) the severe irritability and twitching seen in uraemic patients treated with pethidine (meperidine) are associated with high levels of its norpethidine metabolite; (c) the severe muscle weakness and tenderness seen in patients with renal failure receiving cloflbrate are associated with excessive accumulation of the free acid metabolite of cloflbrate; (d) patients with severe renal insufficiency taking allopurinol appear to experience a higher incidence of side effects, possibly due to the accumulation of oxipurinol; (e) hydroxyamylobarbitone has been incriminated as the cause of impaired cognitive function in uraemic patients given amylobarbitone (amobarbital); and (f) methyldopamine may be responsible for the enhanced sensitivity to methyldopa seen in patients with impaired renal function.

Chemically highly reactive (mainly oxidised) metabolites of ingested foreign compounds are thought to mediate many different types of serious toxicity including carcinogenesis, mutagenesis, dysmorphogenesis and cellular necrosis. The chemical instability of this type of metabolite and its covalent binding to cellular macromolecules is suspected as initiating these conditions. 2-Aminonaphthylene, benzidine and 4-aminobiphenyl are aromatic amines that are known bladder carcinogens in man. The hydroxylamine metabolites are viewed as the first step in the metabolic activation of these aromatic amines. Genetic slow acetylators may be more at risk for bladder cancer from these amines than rapid acetylators. Carcinogenic polycyclic aromatic hydrocarbons, such as benzo(a)pyrene, require metabolic activation, probably to epoxide-diols, to elicit their pharmacological effects. Individuals with higher aryl hydrocarbon hydroxylase activity in their cultured, mitogen-activated peripheral lymphocytes may have an increased risk for certain cancers including bronchogenic carcinoma. Epoxide-diol metabolites of benzo(a)anthracene, but not the parent compound, are highly mutagenic in the Ames test without the need for an oxidising system.

An epoxide metabolite of phenytoin, cyclophosphamide and benzo(a)pyrene is believed responsible for the dysmorphogenic effect of the parent compounds. Also, paracetamol (acetaminophen)-induced cellular necrosis in the liver is believed due to a highly reactive oxidised metabolite. Intravenous N-acetylcysteine is an effective agent against paracetamolinduced hepatic necrosis, provided treatment is begun within 8 hours of paracetamol overdosage. Finally, the major antigenic determinant in penicillin-induced allergy is a penicilloyl-protein conjugate.

Monitoring plasma levels of drugs can be an important guide to therapy. However, if a drug has a chemically stable active metabolite, determination of the parent drug alone may cause misleading interpretations of blood level measurements. The plasma level of the active metabolite should also be determined and its concentration-response and time-action characteristics taken into account in any clinical decision based on drug level monitoring.

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  1. Department of Pharmacology, Cornell University Medical College, 1300 York Avenue, New York, NY, 10021, USA

    Dennis E. Drayer

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Drayer, D.E. Pharmacologically Active Metabolites of Drugs and Other Foreign Compounds. Drugs 24, 519–542 (1982). https://doi.org/10.2165/00003495-198224060-00003

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