Cytochromes P450 Involved in Cyclophosphamide, Paclitaxel and Docetaxel Metabolism in Rats

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Abstract
We investigated involvement of cytochromes P450 (CYPs) of rat liver microsomes in metabolism of two anticancer drugs, paclitaxel (PCT) and docetaxel (DTX), by an indirect method. This method is based on the presumption that the compound competitively inhibiting oxidation of the CYP-selective substrate should also be a substrate for the CYP enzyme. The validity of this approach was confirmed using the model drug, cyclophosphamide (CPA). Indeed, CPA competitively inhibited oxidation of substrates specific for CYP2B1 and CYP3A1/2, enzymes previously reported to be capable of metabolizing CPA. Using this method, we identified CYP enzymes participating in PCT and DTX metabolism. The CYP2D1/2/3 and CYP3A1/2 are enzymes oxidizing PCT while CYP3A1/2 and CYP2E1 are responsible for metabolism of DTX. Here, we report a suitable method serving for easy and fast estimation of CYP enzymes involved in drug metabolism.