AGE AND SEX-DEPENDENT PHARMACOKINETICS OF CYCLOSPORINE IN THE RAT AFTER A SINGLE INTRAVENOUS DOSE

The dependency of cyclosporine (CyA) pharmacokinetics on the age (10 a nd 40-week-oId) and the gender was studied in Wistar rats who were giv en 10 mg/kg dose of the drug intravenously. CyA levels in whole blood were analyzed by a specific fluorescence polarization immunoassay (Abb ot TDx). Blood concentration vs time profiles were characterized by re sorting to compartmental and noncompartmental methods. The first appro ach showed that the best model fitting experimental data was a three-c ompartment open model with first-order kinetics. It indicated that the drug undergoes extensive distribution in a wide variety of tissues. T he mean half-lives corresponding to lambda(1) and lambda(2) phases coi ncided in all groups and lasted on average 0.22 and 4.30 h, respective ly. The mean volume of distribution at steady-state depended mainly on the rats gender and age, indicating values of 2.64 +/- 0.37 l/kg for older males as compared to 2.03 +/- 0.29, 1.71 +/- 0.12, and 1.87 +/- 0.16 l/kg for young males and females and 40-week-old females, respect ively. Drug elimination rates ranged from 0.019 to 0.123 h(-1) and man ifested a marked dependency on both, the gender and the age. The bioav ailability (AUC(0-infinity)) was higher for males (81.06 +/- 8.31 and 139.62 +/- 41.34 mu g.h per mi vs 50.19 +/- 2.10 and 49.65 +/- 5.68 mu g.h per mi) while the systemic blood clearance (CL) was significantly lower for males than for females (85 +/- 19 and 109 +/- 3 ml/h per kg vs 198 +/- 9 and 205 +/- 29 ml/h per kg). No statistically significan t differences were detected between compartmental and noncompartmental parameters by paired t-tests. Therefore, the results demonstrate that female rats clear CyA faster than males, probably due to differences in drug metabolism. (C) 1998 Elsevier Science B.V. All rights reserved .