The cyclosporin‐erythromycin interaction: impaired first pass metabolism in the pig

Abstract

The pharmacokinetic interaction between cyclosporin (CsA) and erythromycin has been studied in the weanling pig model. 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. 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. The extraction ratio appears to be concentration‐dependent in that values derived from Cmax (high concentrations) were greater than those from AUC (average concentrations). 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. 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.

Comparison of Pharmacokinetics of Cyclosporine A in Cadaveric and Living- Related Renal Transplant Recipients and in an Experimental Rat Model of Renal Failure

“…CyA has high binding characteristics to plasma proteins, and the hepatic extraction ratio of CyA is high [22]. The protein binding of drugs is considered to be a factor altering PK properties, such as distribution and clearance.…”

Effect of plasma uric acid on pharmacokinetics of cyclosporine A in living-related renal transplant recipients and pharmacokinetic study in rats with experimental hyperuricaemia

“…In our recent study, similar results were obtained in renal failure model rats, showing a high UA level, prepared by ischaemia‐reperfusion injury, as described earlier. On the contrary, CyA binds strongly to plasma proteins, and the hepatic extraction ratio of CyA is high (24). Protein binding of drugs is considered a factor altering CyA PK properties such as distribution and clearance.…”