Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction

Abstract

The pharmacokinetics of cyclosporine was studied in six healthy volunteers after administration of the drug orally (10 mg/kg) and intravenously (3 mg/kg) with and without concomitant rifampin administration. Both blood and plasma (separated at 37 degrees C) samples were analyzed for cyclosporine concentration. For blood and plasma, respectively, clearances of cyclosporine were calculated to be 0.30 and 0.55 L/hr/kg, values for volume of distribution at steady state were 1.31 and 1.68 L/kg, and bioavailabilities were 27% and 33% during the pre-rifampin phase. Post-rifampin phase clearances of cyclosporine were 0.42 and 0.79 L/hr/kg, values for volume of distribution at steady state were 1.36 and 1.35 L/kg, and bioavailabilities were 10% and 9% for blood and plasma, respectively. Rifampin not only induces the hepatic metabolism of cyclosporine but also decreases its bioavailability to a greater extent than would be predicted by the increased metabolism. The decreased bioavailability most probably can be explained by an induction of intestinal cytochrome P450 enzymes, which appears to be markedly greater than the induction of hepatic metabolism.

Marked enhancement by rifampicin and lack of effect of isoniazid on the elimination of quinine in man.

“…The increased elimination of quinine in subjects receiving rifampicin is consistent with induction of CYP3A-mediated metabolism. Similar findings have been reported for quinidine [9], and cyclosporine [8], also metabolised by CYP3A.…”

“…Quinine is widely used to treat malaria in endemic phylline, antipyrine, hexobarbitone and cyclosporine malaria areas where Plasmodium falciparum is resist- [2][3][4][5][6][7][8]. It has been shown that rifampicin decreases the ant to chloroquine.…”

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

“…On the other hand, CYP3A accounts for about 30 and 70% of total CYP activity in the liver and small intestine, respectively [12][13][14], and intestinal first-pass metabolism mediated by CYP3A has been shown to be clinically relevant for several drugs, including cyclosporin A [15,16]. However, it remains to be fully clarified whether P-gp and/or CYP3A controls the oral bioavailability of cyclosporin A by limiting absorption from the small intestine.…”

Relevance of induction of human drug‐metabolizing enzymes: pharmacological and toxicological implications

“…Again in such studies extent than would be predicted from the increase in it is essential that both qualitative and quantitative hepatic metabolism; this is due to an additional aspects of induction are considered. induction of intestinal P450 enzymes that appears greater than the induction of hepatic metabolism [70 ].…”