PMID: 8595701Dec 1, 1995Paper

Alternative cyclosporine metabolic pathways and toxicity

Clinical Biochemistry
U Christians, K F Sewing

Abstract

There are some indications from clinical studies (41,43) for aberrant cyclosporine metabolism resulting in formation of potentially toxic metabolites. When the activity of cytochrome P450 3A enzymes is low, more substrate is available for hypothetical alternative pathways of cyclosporine. There are several reasons for low P450 3A activity in a liver graft such as inter-individual genetic variability (43,49,84), cold ischemia and reperfusion damage, changes of the P450 activity during cholestasis (85) or other liver diseases (86), the influence of cytokines (87) and drug interactions such as inhibition or enzyme induction (88). Furthermore, low concentrations of cytochrome P450 3A influence the cyclosporine blood trough concentrations. The P450 3A concentration as estimated by the erythromycin breath test can be used to calculate the initial cyclosporine dose required to obtain cyclosporine blood trough concentrations in the therapeutic window (89). In vitro such alternative pathways comprising 3-methylcholanthrene-inducible (44,46,47) and/or ethinyl estradiol-inducible cytochrome P450 enzymes (48) could be identified and resulted in production of cyclized cyclosporine metabolites. The exact identification of the P450 enzymes in...Continue Reading

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