A SINGLE-DOSE PHARMACOKINETIC STUDY OF 13-CIS RETINOIC ACID (ISOTRETINOIN, RO-04-3780) IN THE PREGNANT NEW-ZEALAND RABBIT USING INTRAVENOUS-INFUSION

The pharmacokinetics of 13-cis retinoic acid in the pregnant New Zeala nd rabbit were determined after intravenous administration. This drug displayed linear pharmacokinetics in this species. Noncompartmental ph armacokinetic analyses were performed on individual data sets and an a verage value determined for each parameter (n = 3/dose group). The mea n V-dss, CL and t(1/2) 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 t he 5.0 mg/kg dose group was modeled to a three-compartment model with elimination occurring from the first compartment only. The pharmacokin etic parameters of AUG, CL, V-dss, MRT and the effective half-life cal culated from compartmental analysis were similar to those obtained fro m noncompartmental analysis. The noncompartmental pharmacokinetic para meters determined for the rabbit were found to compare favorably with those reported for the monkey. The monkey is considered to be an appro priate specie for modelling the pharmacokinetics of 13-cis retinoic ac id in humans. We propose that since the pharmacokinetics of 13-cis ret inoic acid are similar between the two species ind 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 o f 13-cis retinoic acid therapy in humans.