Disposition of 3H-enisoprost, a gastric antisecretory prostaglandin, in healthy humans.
1. After oral administration of 3H-enisoprost (450 micrograms) 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 [(+/-)11 alpha, 16 zeta-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 beta-oxidation, omega-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-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-3 alpha-hydroxy-5-oxo-1 alpha-cyclopentanyl]propanoic acid (SC-41411; 3.6% dose), (+/-)3-[3 alpha,5-dihydroxy-2 beta-(4-hydroxy-4-methyl-1E-octenyl)-1 alpha-cyclopentanyl]propanoic acid (SC-41411 PGF analogue; 4.8% dose), (+/-)3-[2 beta-(8-carboxy-4-hydroxy- 4-methyl-1E-octenyl)-3 alpha-hydroxy-5-oxo-1 alpha-cyclopentanyl] propanoic acid (SC-41411-16-carboxylic acid; 22% dose), (+/-)3-[2 beta-(8-carboxy-4- hydroxy-4-methyl-1E-octenyl)-3 alpha,5-dihydroxy-1 alpha-cyclopentanyl] propanoic acid (SC-41411 PGF analogue-16-carboxylic acid; 8.5% dose) and its gamma lactone (2.6% dose). 5. These metabolites were also identified chromatographically in plasma, as were SC-36067, (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-1 alpha- cyclopent-3-enyl]propanoic acid and (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-cyclopent-1- propanoic acid. 6. Some 5-10% of the dose was excreted in urine as tritiated water, indicating that oxidation of the 11 alpha-hydroxy group in SC-36067 or its metabolites also occurred.
G. D. Searle & Co. Ltd, High Wycombe, Bucks, UK.
L M
LM
Allan
A J
AJ
Hawkins
C W
CW
Vose
J
J
Firth
R D
RD
Brownsill
J A
JA
Steiner
D000328:Adult; D000527:Alprostadil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000032:analysis; D008401:Gas Chromatography-Mass Spectrometry; D005744:Gastric Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D011465:Prostaglandins, Synthetic / Q000008:administration & dosage / Q000493:pharmacokinetics*
D011465:Prostaglandins, Synthetic; D000527:Alprostadil; C054594:enisoprost