Evaluation of Factors to Decrease Bioavailability of Cyclosporin A in Rats with Gentamicin-Induced Acute Renal Failure

Abstract

Focusing on the disposition of cyclosporin A (CsA) in the liver and intestine, effects of gentamicin-induced acute renal failure (ARF) on the decreased oral bioavailability of CsA were evaluated in rats. The area under the CsA concentration-time curve (AUC) in ARF rats after oral administration (5 mg/kg) significantly decreased by 43% as compared to the control, while the apparent oral clearance significantly increased by 76% of the control. The portal AUC of CsA in ARF rats with bile flow decreased by 67% as compared to the control rats. Without bile flow, the portal AUC of CsA in control rats decreased by 50% as compared to those with bile flow, whereas ARF rats without bile flow showed no notable change as compared to those with bile flow. The AUC of CsA mono-oxidative metabolite via CYP3A (M-OH) in ARF rats after oral or intravenous administration increased significantly by 84% or 241%, respectively, while there was no difference in the portal M-OH between control and ARF rats, suggesting that the elimination of M-OH was prolonged because of nephrotoxicity. Although the exsorption clearance of CsA from the blood circulation to the intestine after intravenous administration to ARF rats decreased significantly as compared to the control; and basolateral-to-apical transport of CsA through Caco-2 monolayers was significantly retarded in the presence of uremic toxins, there was no significant change in the total body clearance of CsA between ARF and control rats. Moreover, there were no effects of uremic toxins on the protein binding of CsA in plasma. These observations suggest that hepatic or intestinal CYP3A and P-glycoproteine (P-gp) are not likely to be concerned with lowering the oral bioavailability of CsA, and that bile function under the ARF condition induced by gentamicin is responsible for a marked decrease in the fraction absorbed of CsA in the small intestine.

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

“…In the rats, hepatic function was not impaired, as judged from the laboratory data, whereas increases in the values of serum creatinine and BUN indicated an appreciable impairment of renal function by the high-AMB treatment (Table 2). However, the increases of serum creatinine and BUN were not large compared with the increases of about 3-to 5-fold and 2-to 5-fold in model rats with gentamicin-or glycerol-induced renal failure, respectively [22][23][24]. Therefore, we considered that the AMB-induced renal impairment was not great even in the high-AMB group, and may have had only a slight influence on the excretion of CyA, which is metabolized mainly by CYP3A.…”

“…There are some reports indicating that the disposition kinetics of CyA is influenced by renal failure in rats. Shibata et al [22] reported that CYP3A and P-gp in liver and intestine are not likely to be involved in lowering the oral bioavailability of CyA in gentamicin-induced acute renal failure, and that a change in bile function is responsible for the marked decrease. Huang et al [23] reported that the expression level of P-gp in rats with glycerol-induced acute renal failure was increased 2.5-fold in the kidney, but not in the liver or brain.…”

An analytical method for cyclosporine using liquid chromatography–mass spectrometry

“…Li et al (2007) described a CyA LC-MS assay for use in monkey and rat plasma, although cyclosporine C was used as IS. Similarly Shibata et al (2004) reported a method using cyclosporine D as IS; as mentioned above, neither of these two IS is available commercially. In the current method, amiodarone was employed as IS.…”

“…For research purposes, the specific measurement of CyA is possible using one of a number of valuable highperformance liquid chromatographic (HPLC) methods (Burckart et al, 1990;Chimalakonda et al, 2002;McBride et al, 1989). More specific and sensitive liquid chromatography-mass spectrometry (LC-MS) methods have been reported for the measurement of CyA in various matrices, although many incorporate solid phase extraction (Zaater et al, 2005) or commercially unavailable internal standards (IS) such as cyclosporine C and D (Li et al, 2007;Shibata et al, 2004;Simpson et al, 1998), which can pose challenges to their widespread use.…”

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

“…This mechanism is still unclear. On the other hand, it has been reported that CyA absorption decreased in rats with several drug-induced acute renal failure, and that decreased bile secretion was the main reason for reducing the absorption of CyA in gentamicin-induced acute renal failure rats [4,5]. Therefore, it is speculated that renal injury after CRT affects the PK of CyA.…”