Evaluation of factors to decrease bioavailability of cyclosporin A in rats with gentamicin-induced acute renal...

Area of Science:

• Pharmacology
• Nephrology
• Drug Metabolism

Background:

• Cyclosporin A (CsA) is a critical immunosuppressant with variable oral bioavailability.
• Acute renal failure (ARF) can impact drug disposition, potentially affecting CsA efficacy.
• Understanding CsA pharmacokinetics in ARF is crucial for optimizing patient treatment.

Purpose of the Study:

• To investigate the effects of gentamicin-induced ARF on CsA disposition in rats.
• To elucidate the mechanisms underlying the altered oral bioavailability of CsA in ARF.
• To assess the roles of hepatic/intestinal transporters and bile function in CsA absorption during ARF.

Main Methods:

• Oral and intravenous administration of CsA (5 mg/kg) in control and ARF rats.
• Measurement of CsA and its metabolite (M-OH) concentrations in plasma and bile.
• Assessment of CsA transport across Caco-2 cell monolayers in the presence of uremic toxins.
• Evaluation of CsA protein binding and exsorption clearance.

Main Results:

• Oral bioavailability of CsA decreased by 43% in ARF rats, with a 76% increase in apparent oral clearance.
• Portal CsA concentrations were significantly reduced in ARF rats with bile flow.
• Elimination of the CsA metabolite (M-OH) was prolonged in ARF rats, indicating nephrotoxicity.
• Basolateral-to-apical transport of CsA was impaired by uremic toxins, but total body clearance remained unchanged.

Conclusions:

• Gentamicin-induced ARF significantly lowers CsA oral bioavailability in rats.
• Impaired bile function, rather than alterations in hepatic/intestinal CYP3A or P-glycoprotein, is the primary cause of reduced CsA absorption.
• Nephrotoxicity prolongs the elimination of CsA metabolites, suggesting potential drug accumulation risks.