Abstract
Drug metabolism is a major determinant of drug clearance, interindividual pharmacokinetic differences and, indirectly, of the clinical efficacy and toxicity of drugs. Altered pharmacokinetics can result in inadequate concentration of the drug at the site of action and/or great variations in clinical response. Therefore, the development of a new drug requires not only an exhaustive characterisation of its pharmacological activity, but also knowledge of major enzymes involved in metabolite formation, and the potential enzyme inhibiting or enzyme inducing properties of the drug. Multi-drug therapy is not uncommon in clinical practice. Simultaneous administration of several drugs may result in metabolic drug-drug interactions having pharmacological and/or toxicological implications. As drugs are metabolised by a limited number of enzymes, they can compete each other as substrates for the same enzyme. Thus, competitive/non-competitive/irreversible inhibition of drug-metabolising enzymes by one of the therapeutic agents will result in elevations in plasma/tissue concentrations of the other drugs. For compounds with a narrow therapeutic index, this can lead to overdosage symptoms and/or toxicity. Cytochrome P450 (P450) enzymes are major players in the oxidative metabolism of therapeutic agents and, consequently, the most common mechanism underlying drug-drug interactions is the inhibition of P450 activities. Several drugs in common use cause large increases in exposure to other drugs. As this is an undesirable feature for a drug candidate, information about P450 inhibition by the compound should be obtained before a drug candidate is considered for the clinical stages of development. A combination of biochemical advances in the understanding of the function and regulation of drug-metabolising enzymes, in particular P450s, and automated analytical technologies are revolutionising drug metabolism research.
Keywords: Cytochrome P450, drug-drug interaction, hepatocytes, irreversible inhibitors, microsomes, reversible inhibitors
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