Pharmacokinetics of oestriol after repeated oral administration to dogs

The aim of the present study was to investigate the pharmacokinetics of oestriol in plasma in the dog after repeated oral administration of oestriol tablets, a preparation intended for the treatment of urinary incontinence in the bitch. The study was performed in six healthy, entire, adult female beagle dogs. The bitches were treated once daily with two tablets, containing 1 mg oestriol per tablet, for seven consecutive days (days 1-7). Blood samples were taken from the jugular vein before treatment, frequently on days 1, 3 and 7 of the treatment period and daily just before (C(trough)) and 1 h after dosing (C(t=1h)). During the washout period samples were taken at a 24 h interval up to four days post-treatment. Oestriol concentrations were determined in plasma by radioimmunoassay. Pharmacokinetic parameters, AUC, C(max) and t(max), were determined from the plasma concentration-time curves using non-compartmental methods. The between animal variation in C(max) and the AUC was high. Individual values of the C(max) varied from 206 pg/ml (day 1) to 1128 pg/ml (day 7) and the AUC(0-24h) from 789 pg x h/ml (day 1) to 5718 pg x h/ml (day 7). t(max) occurred within 1 h. The mean C(trough) value was slightly above the pre-treatment level ( 38+/-2 pg/ml vs. 18+/-5 pg/ml). Within 48 h after the last treatment the concentrations had returned to the pre-treatment values. C(max) and C(trough) did not increase during the treatment period, indicating that no accumulation occurred. A shoulder in the concentration-time curve around 8-12 h after treatment strongly suggested the existence of enterohepatic recirculation (EHR). The average relative contribution of the EHR to the AUC(0-24h) was estimated to be 22%, 38% and 44% on days 1, 3 and 7, respectively. These mean values were calculated from five animals per time point, because one dog failed to show EHR on days 1 and 3 and was therefore excluded from the calculations.