Clinical Implications for Drug Metabolism and ToxicityThere is a well established clinical importance of hepatic cytochrome P450 in drug metabolism. Antidepressants and neuroleptic drugs show large interindividual toxicity due to genetically variable metabolism catalyzed by P450s and there are clinical implications of variable P450 activities for metabolism of anti-arrythmic drugs. Toxic side effects can occur with the administration of two drugs metabolized by the same target P450. An example is the co-administration of terfenadine and erythromycin, both interactive with 3A4 which caused severe toxicity. The MAb system identifies drugs metabolized by a single P450 or multiple P450s and partner drugs metabolized by a common P450, which may thereby result in toxicity. The MAbs determine cytochrome P450 substrate and product specificity, interindividual variation in P450 based drug metabolism in liver and other tissues and the effects of P450 inducers, inhibitors, genetic factors, ethnic differences, age, gender, developmental and nutritional states and environmental factors.Polymorphic genetically defective P450 genes can be identified by genomic methods and Mab based proteomic methods which quantitatively measure P450 gene expression at the functional protein level. The Mab system identifies drugs metabolized by polymorphic P450s missing or defective in certain populations. The clinical use of those drugs would depend on the relative amount of the drug metabolized by other non- polymorphic P450s. The MAb system can identify and develop a list of drugs that can be used in vivo for phenotyping an individuals P450 profile. In vivo determination of the P450 isoform phenotype requires that the marker drugs metabolic pathway be entirely catalyzed by a single P450. Identification of a drug for its P450 based metabolism coupled with a knowledge of the phenotype of the recipient individual will be clinically useful for drug choice, dosage, and the prediction of the toxicity of a drug or drug combinations and the drugs P450 related efficacy.From the Present to the FutureThe MAb system for analyses of drug and non-drug xenobiotic metabolism is comprehensive for the major isoforms of human P450s, simple to use, and yields quantitative measurements. The MAbs are easily obtainable, and are pure highly specific antibody reagents that are stably derived from potentially immortal hybridomas. There will be a time when toxicity resulting from a drugs metabolism will be minimized out of existence. The administration of a drug will be based on a knowledge of the enzymatic basis of its metabolism coupled with identification of the recipient individuals phenotype for the enzymes metabolizing the drug. The library of MAbs should prove of large use towards that goal and in the process of Drug Discovery. - Cytochrome p, 0, Human P, 0 phenotyping, Drug Metabolism, Drug toxicity, Specific Inhibitory Monoclonal antibodies, Specific Inhibitory P, 0 Expression, Polymorphism,
