The cyclosporin-erythromycin interaction: impaired first pass metabolism in the pig.
1. The pharmacokinetic interaction between cyclosporin (CsA) and erythromycin has been studied in the weanling pig model. 2. Blood CsA and metabolite-1 (M1) concentrations were monitored by high performance liquid chromatography in portal, hepatic and jugular venus blood before and after treatment with erythromycin stearate for 7 days. 3. Erythromycin significantly increased maximum concentration (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC) of CsA in the peripheral circulation. This was accompanied by a significant reduction in the hepatic extraction ratio calculated from portal and hepatic Cmax and AUC data. 4. The extraction ratio appears to be concentration-dependent in that values derived from Cmax (high concentrations) were greater than those from AUC (average concentrations). 5. Time to Cmax (tmax) and t1/2 of CsA were essentially unchanged and no significant changes were observed in peripheral M1 kinetics apart from a small increase in tmax. 6. The pharmacokinetic changes observed in the pig suggest that the CsA-erythromycin interaction is caused by inhibition of hepatic metabolism and the impact of inhibition is greatest during first-pass when CsA concentrations are at their highest.
Freeman
D J
DJ
Robarts Research Institute, University Hospital, London, Ontario, Canada.
Grant
D R
DR
Carruthers
S G
SG
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004917:Erythromycin / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D013552:Swine
D004917:Erythromycin; D016572:Cyclosporine