IS CYCLOSPORINE-A AN INHIBITOR OF DRUG-METABOLISM

1. The potential for a drug interaction between cyclosporin A and midazolam was investigated since both compounds appear to be metabolized by the same cytochrome P‐450 isoenzyme. 2. In vitro evaluation of the binding of cyclosporin A to rat microsomal cytochrome P‐450 indicated a Ks‐value of 0.4 microM. In further studies with rat liver microsomes IC50‐values of 6, 8 and 70 microM cyclosporin A were determined for the inhibition of the metabolism of midazolam to its alpha‐OH‐,4‐OH‐ and di‐OH‐metabolites, respectively. 3. Comparative studies with human liver microsomes indicated IC50‐values of approximately 300 microM for the formation of alpha‐OH‐midazolam and of 65 microM for the formation of 4‐OH‐midazolam. 4. The pharmacokinetics of a single intravenous dose of midazolam (0.075 mg kg‐1) was studied in nine patients receiving cyclosporin A to prevent rejection of their transplanted kidneys. The average steady state blood concentrations of cyclosporin A, measured by r.i.a. using a specific monoclonal antibody, varied during a dosing interval between 175 and 600 ng ml‐1. 5. In these patients the hepatic elimination of midazolam was characterized by a mean t1/2 (+/− s.d.) of 2.3 +/− 1.2 h and a plasma clearance (CL) of 414 +/− 95 ml min‐1. These values were not different from those of normal human subjects (t1/2 = 1.5 to 4 h, CL = 350 to 700 ml min‐1). 6. From the results of the in vitro experiments it is concluded that cyclosporin A may potentially inhibit drug metabolism.(ABSTRACT TRUNCATED AT 250 WORDS) 1990 The British Pharmacological Society