Is cyclosporin 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)
Li
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Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, FRG.
Treiber
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Meinshausen
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Wolf
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Werringloer
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Klotz
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U
D000328:Adult; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003524:Cyclosporins / Q000097:blood / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008874:Midazolam / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D003524:Cyclosporins; D006993:Hypnotics and Sedatives; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D008874:Midazolam