A single dose pharmacokinetic study of 13-cis retinoic acid (Isotretinoin, Ro 04-3780) in the pregnant New Zealand rabbit using intravenous infusion

Abstract

The pharmacokinetics of 13-cis retinoic acid in the pregnant New Zealand rabbit were determined after intravenous administration. This drug displayed linear pharmacokinetics in this species. Noncompartmental pharmacokinetic analyses were performed on individual data sets and an average value determined for each parameter (n = 3/dose group). The mean Vdss, CL and t12 for the 0.5 mg/kg dose group were 534.0 ± 144.8 ml/kg, 139.2 ± 41.0 ml/h/kg and 3.8 ± 0.8 h, whereas for the 5.0 mg/kg dose group these parameters were 676.3 ± 145.5 ml/kg, 169.8 ± 18.9 ml/h/kg and 4.2 ± 1.3 h, respectively. The mean data from the 5.0 mg/kg dose group was modeled to a three-compartment model with elimination occurring from the first compartment only. The pharmacokinetic parameters of AUC, CL, Vdss, MRT and the effective half-life calculated from compartmental analysis were similar to those obtained from noncompartmental analysis. The noncompartmental pharmacokinetic parameters determined for the rabbit were found to compare favorably with those reported for the monkey. The monkey is considered to be an appropriate specie for modelling the pharmacokinetics of 13-cis retinoic acid in humans. We propose that since the pharmacokinetics of 13-cis retinoic acid are similar between the two species and the rabbit displays great sensitivity to the teratogenic effects of 13-cis retinoic acid that it may be a good animal model to use to assess the risk/benefit of 13-cis retinoic acid therapy in humans.