Mechanism of decrease of oral bioavailability of cyclosporin A during immunotherapy upon coadministration of amphotericin B

Abstract

Running Title: Interaction of oral cyclosporin A/amphotericin B Abbreviations: CyA, cyclosporin A; AMB; amphotericin B; BA, bioavailability; CYP, cytochrome P450; P-gp, P-glycoprotein; DEX, dexamethasone; ALT, alanine aminotransferase; AST, aspartate aminotransferase; γ-GTP, γ-glutamyltranspeptidase; BUN, blood urea nitrogen; AUC 0-24h , area under the blood concentration-time curve from 0 to 24 h; MRT, mean residence time; CL tot , total clearance; Vd ss , distribution volume at the steady-state -1-ABSTRACT: The trough level of blood concentration of cyclosporin A (CyA) in a patients receiving immunotherapy was observed to decrease following coadministration of amphotericin B (AMB). We confirmed this clinical observation in experiments using Wistar rats intravenously given AMB (1.5 or 3.0 mg/kg) or saline (control) for 4 days, followed by CyA (10 mg/kg). The blood concentration of CyA after iv or po administration in both AMB groups was significantly decreased compared with the control. The oral bioavailability of CyA after 1.5 or 3.0 mg/kg AMB treatment was decreased to 67 or 46%, respectively, of that of the control group. AMB treatment increased the expression levels of mdr1a and mdr1b mRNAs in duodenum to about 3 times the control, and expression of CYP3A2 mRNA in liver was increased to about twice the control. The induction of their mRNAs by AMB treatment increased the level of P-gp and CYP3A2 protein to about twice the control. These findings suggest that the oral bioavailability of CyA is reduced as a result of both increased efflux transport via P-glycoprotein in the duodenum and an increased firstpass effect of CYP3A2-mediated hepatic metabolic activity, induced by AMB. We suggest that careful monitoring of CyA levels is necessary in the event of AMB administration to patients receiving immunotherapy with CyA.

In Vitro and In Vivo Evidence for Amphotericin B as a P-Glycoprotein Substrate on the Blood-Brain Barrier

“…Consistent with our results, interaction between AMB and P-gp has been suggested by other pieces of evidence from studies on animal intestines (13,14,25). In a study by Ishizaki and colleagues, the oral bioavailability of cyclosporine was decreased after coadministration of AMB in Wistar rats, presumably due to the increased P-gp expression induced by AMB at the duodenum (14). Second, another research group demonstrated enhanced gastrointestinal absorption of AMB through formulating it in the oral lipid-based delivery system Peceol, which was able to decrease P-gp-mediated drug efflux by downregulating mdr1 mRNA in Caco-2 cells, also suggesting an interaction between this agent and P-gp (13,26).…”

“…2). Consistent with our results, interaction between AMB and P-gp has been suggested by other pieces of evidence from studies on animal intestines (13,14,25). In a study by Ishizaki and colleagues, the oral bioavailability of cyclosporine was decreased after coadministration of AMB in Wistar rats, presumably due to the increased P-gp expression induced by AMB at the duodenum (14).…”

“…The inhibition of P-gp has been demonstrated to increase the CNS concentrations of numerous agents, highlighting the therapeutic potential for P-gp inhibitors as synergists to improve BBB penetration of substance drugs (11). It is currently unclear whether P-gp is also involved in the BBB transportation of AMB, except that two earlier studies suggested relationships between the rat intestinal P-gp transporter and AMB (13,14). This study aims to further investigate the effect of P-gp inhibitors in the brain uptake of AMB in vitro and in vivo and to explore the potential therapeutic effect of AMB with P-gp inhibition in a cryptococcal meningitis murine model.…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…36 This is mediated via increased expression of the multidrug resistance gene MDR1 in the duodenum causing increased levels of the MDR1 gene product P-gp, 36 but it is not known if liposomal amphotericin has a similar effect. This results in increased efflux of ciclosporin and reduced plasma levels.…”

Renal Handling of Amphotericin B and Amphotericin B-Deoxycholate and Potential Renal Drug-Drug Interactions with Selected Antivirals

“…One study documented the drug-drug interactions of AmB and P-glycoprotein in the gastrointestinal tract (GIT). The authors demonstrated that AmB treatment significantly increased the level of P-glycoprotein, which resulted in a decrease in the oral bioavailability of cyclosporine in rats (30). Additional information on AmB interactions with efflux transporters, however, is not available; therefore, further studies should be performed.…”