Cyclosporine pharmacokinetics and effect in the Type I diabetic rat model

Abstract

Recent clinical studies have demonstrated the potential benefit of the T-cell-specific immunosuppressant, cyclosporine, in the treatment of Type I insulin-dependent diabetes. In the present study, steady-state cyclosporine pharmacokinetics, fasting glucose and insulin levels and renal function were examined in stable insulin-dependent diabetic rats and compared to non-diabetic rats. Mean creatinine clearance 30 days following diabetes induction was not significantly different from saline controls. Cyclosporine treatment (5 mg/kg/day i.v. for 13 days) did not significantly alter creatinine clearance in either group; however, renal function of vehicle-treated diabetic rats was markedly reduced compared to other groups. Serum insulin concentrations were significantly greater in diabetic rats treated with cyclosporine compared to the control group (35.1 +/- 22.7 vs. 16.0 +/- 8.1 microU/ml; P less than 0.05). Glucose levels were proportionately reduced in diabetic rats treated with cyclosporine. Area under the concentration-time curve, half-life and volume of distribution of cyclosporine were significantly reduced in diabetic rats compared to non-diabetic controls. In summary, the pharmacokinetics and pharmacodynamics of cyclosporine were significantly different in the insulin-dependent diabetic rat model compared to normal controls. Furthermore, short-term cyclosporine therapy reduced the extent of experimental diabetic nephropathy observed in this model.

Opposite Effect of Diabetes Mellitus Induced by Streptozotocin on Oral and Intravenous Pharmacokinetics of Verapamil in Rats

“…Our previous study showed that the exposure to baicalin was increased after oral administration in diabetic rats but decreased after intravenous administration . Another report demonstrated that cyclosporine in diabetic rats after intravenous administration was significantly lower than that in control rats (Brunner et al, 1989). In contrast, the AUC of cyclosporine in diabetic rats after an oral dose was approximately 65% greater than that in control rats (Ogata et al, 1996).…”

Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus

“…[155,156] After the intravenous administration of 5 mg/kg per day ciclosporin for 13 days to male CD DMIS rats on the 35th day, their AUC values became significantly smaller (by 31.9%) than that of the controls. [157] This could possibly have been due to the significantly faster in-vitro CL int for the disappearance of ciclosporin (not measured) in the DMIS rats. This was because ciclosporin is a drug with a low hepatic extraction ratio drug in rats (its 'indirect' hepatic first-pass effect was found to be 14.7%).…”

“…This was because ciclosporin is a drug with a low hepatic extraction ratio drug in rats (its 'indirect' hepatic first-pass effect was found to be 14.7%). [157] The faster hepatic CL int could have been due to the increase in the protein expression or mRNA levels of hepatic CYP3A1, 3A2, and 3A1/2 in the DMIS rats (Table 1). [16,17,21] However, different results have been reported.…”

“…Comparable intravenous AUC 0-12 h of doxorubicin in DMIS rats [153] 20 Ciclosporin CYP3A1/2 in rats Significantly smaller, unchanged, and significantly greater intravenous AUC values of ciclosporin in DMIS rats [8,157,158]…”

Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

“…Another example is cyclosporin A. Cyclosporin A is also a substrate of CYP3A, MRP2, P-gp, OATP1B1 and BCRP. Significantly increased systemic clearance of cyclosporin A in diabetic rats [77] should be attributed to the net effect of alterations in these transporters and CYP3A. Methotrexate transport in the liver is mediated by various transporters such as OATP1B1, MRP2, BCRP and OAT2.…”