The interaction between cyclosporin A and erythromycin studied by means of an isolated perfused rat liver model.
The isolated perfused rat liver model was successfully used to study the clinical interaction observed between cyclosporin A (CsA) and erythromycin (ER). Three experimental studies were performed. In a "Control group", isolated rat livers were perfused with 60 micrograms 3H-CsA for 20 min. In an "ER group", isolated rat livers were simultaneously perfused with 60 micrograms 3H-CsA and 6.0 mg ER. In an "ER ind group", rats were treated with ER for 5 days, conditions under which the P450IIIA gene subfamily, principally involved in CsA metabolism, was specifically induced, and isolated rat livers were perfused with 60 micrograms 3H-CsA for 20 min. Biological parameters of the liver model such as biliary flow, oxygen consumption and pH were similar whatever group of animals. Biliary excretion of total radiolabel (sum of CsA and all the metabolites = CsAT) was similar in both the "Control" and "ER" groups but significantly higher in the "ER ind" group with respectively 8.05 +/- 0.81%, 8.45 +/- 1.93% and 14.54 +/- 2.12% of the entire amount of infused drug excreted during 2 hr. Using a high performance liquid chromatography method which specifically resolves unchanged CsA from its metabolites, we demonstrated that, although similar amounts of radiolabelled material were excreted in both the "Control" and "ER" groups, the CsA/metabolite ratio was lower than 1.0 in the "Control group" and higher than 1.0 in the "ER group", suggesting an inhibition of CsA metabolism by ER in the "ER group". These data could explain the increase in CsA blood levels observed in the clinic following administration of high ER doses and the reversing effect when ER administration is stopped.
Fabre
I
I
INSERM U-278, Laboratory of Pharmacokinetic and Toxicokinetics, Faculty of Pharmacy, Marseille, France.
Richard
B
B
Combalbert
J
J
Fabre
G
G
Cano
J P
JP
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003524:Cyclosporins / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism; D004917:Erythromycin / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects*; D008297:Male; D008954:Models, Biological; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
D003524:Cyclosporins; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System