The Disposition of the Synthetic Prostaglandin Analogue Cloprostenol ('Estrumate') in the rat and marmoset

Abstract

1. Following subcutaneous administration of the synthetic prostaglandin analogue [¹⁴C]cloprostenol to the rat (200μg/kg), the dose was quantitatively recovered from the excreta: 52% of the dose was present in the urine and 43% in faeces. After intravaginal administration (200 μg/kg) 42% of the dose was recovered from the excreta, equally divided between urine and faeces, and 40% (range 25-66%) of the dose was recovered from the site of application. The radiolabelled compounds present in faeces were eliminated initially via the bile.

2. The max. observed plasma concn. of total ¹⁴C in the rat was 84 ng equiv./ml at 30 min after subcutaneous administration of cloprostenol (200 μg/kg). A component which co-chromatographed with cloprostenol on t.l.c. was rapidly cleared from plasma with a half-life of 54 min. After intravaginal administration of cloprostenol (200 μg/kg), low and persistent plasma concn. of ¹⁴C were detected.

3. The metabolic fate of cloprostenol in the rat and marmoset has been studied with radiolabelled and non-labelled drug mixed such that fragments detected by mass spectrometry exhibited characteristic ¹²C: ¹⁴C isotope clusters. Metabolites derived from cloprostenol contained these characteristic doublets.

4. In the rat cloprostenol is metabolized by β-oxidation to tetranor-cloprostenol. Unchanged cloprostenol and a conjugate of tetranor-cloprostenol were minor urinary metabolites. In the rat biotransformation of cloprostenol in the cyclopentane ring occurred; the tetranor acid of 9-keto-cloprostenol was identified in urine. In the marmoset unchanged cloprostenol and dinor-cloprostenol were major urinary components.