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Abstract
1. After oral administration of 3H-enisoprost (450 μg) to five healthy men, as a solution in capsules, peak 3H levels of 5624 ± 566 pg equiv./ml (mean ± S.E.M.) were reached within one hour. No unchanged drug was detected in plasma.
2. Enisoprost was rapidly de-esterified to SC-36067 [(±)11α, 16ζ-dihydroxy-16-methyl-9-oxoprost-4Z, 13E-dien-1-oic acid], a pharmacologically active analogue, which reached peak concentrations of 651±200 pg/ml within 20 min of dosing. SC-36067 was eliminated metabolically, with a half-life of 1.61 h, by a combination of β-oxidation, β-oxidation and 9-keto-reduction.
3. After nine days 59.0±2.98% and 17.4±1.57% of the dose was excreted in urine and faeces respectively. The majority of this excretion was complete in two days.
4. Five urinary metabolites were identified by GC-MS. These were (±)3-[2β-(4-hydroxy-4-methyl-1E-octenyl)-3α-hydroxy-5-oxo-1α-cyclopentanyl]propanoic acid (SC-41411; 3.6% dose), (±)3-[3α,5-dihydroxy-2β-(4-hydroxy-4-methyl-1E-octenyl)-1α-cyclopentanyl]propanoic acid (SC-41411 PGF analogue; 4.8% dose), (±)3-[2β-(8-carboxy-4-hydroxy-4-methyl-1E-octenyl)-3α-hydroxy-5-oxo-1α-cyclopentanyl] propanoic acid (SC-41411-16-carboxylic acid; 22% dose), (±)3-[2β-(8-carboxy-4-hydroxy-4-methyl-1E-octenyl)-3α,5-dihydroxy-1α-cylopentanyl]propanoic acid (SC-41411 PGF analogue-16-carboxylic acid; 8.5% dose) and its γ lactone (2.6% dose).
5. These metabolites were also identified chromatographically in plasma, as were SC-36067, (±)3-[2β-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-1α-cyclopent-3-enyl]propaloic acid and (±)3-[2β-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-cyclopent-1-enyl]propanoic acid.
6. Some 5-10% of the dose was excreted in urine as tritiated water, indicating that oxidation of the 11α-hydroxy group in SC-36067 or its metabolites also occurred.