Pharmacokinetics of prostaglandins.

Naturally occurring prostaglandins (PGs) are rapidly metabolized in the human circulation. For clinical use a number of PG analogues have therefore been developed which are resistant to rapid inactivation. Among these are carboprost, gemeprost and misoprostol. Following intramuscular injection of carboprost, plasma levels peaked after 20 minutes and declined slowly thereafter. In amniotic fluid the half-life was between 31 and 37 hours. Gemeprost is administered vaginally, and maximum plasma levels were reached after 2-3 hours, with detectable levels for at least 6-8 hours. Pharmacokinetic data on misoprostol are available following oral, vaginal and sublingual administration. Following oral treatment, plasma levels peaked at about 30 minutes, while after vaginal administration of the tablets the levels increased gradually and reached maximum levels after 70-80 minutes, but remained detectable for a significantly longer time. After sublingual administration the peak concentration was the same as for oral treatment but declined significantly more slowly. Endocervical administration of PGE(2) might be regarded as a local therapy, while following vaginal administration increased plasma levels of metabolites can generally be found. The plasma profile varies with the vehicle used.

Inhibitory effects of prostacyclin analogue, TFC-132, on aortic neointimal thickening in vivo and smooth muscle cell proliferation in vitro.

Effects of a new prostacyclin analogue, TFC-132, on neointimal thickening following intimal mechanical injury and on the proliferation of cultured aortic smooth muscle cells (SMCs) were studied. The intimal injury was induced by indwelling of polyethylene tubing for 24 h in the rabbit aorta. Rabbits were killed 10 days after drawing out the tubing. TFC-132 (0.6 mg/kg or 1.2 mg/kg) was given orally at 8-h intervals through the experiment. The serum concentrations of the analogue rose significantly 1 and 2 h after administration. The mean intimal thickening in the TFC-132 treated groups was significantly thinner than in the control one. Human aortic SMCs were cultured and 3H-thymidine incorporation into DNA (DNA synthesis) was measured at the varying concentrations of TFC-132. The analogue inhibited DNA synthesis of cultured SMCs at 10(-6) and 10(-5) M. These data indicate that a new prostacyclin analogue, TFC-132, has an inhibitory effect on the neointimal thickening after intimal injury and on the aortic SMC proliferation.

Micro-quantitative determination of ciprostene in plasma by gas chromatography-mass spectrometry coupled with an antibody extraction.

A simple and highly sensitive method has been developed for the determination in plasma of ciprostene, 9 beta-methyl-6 alpha-carbaprostaglandin I2, using gas chromatography-mass spectrometry following solid-phase extraction on an immobilized antibody column. The anti-ciprostene antibody obtained from rabbit serum was coupled to an agarose support matrix, and the immobilized antibody thus prepared was used as an extraction phase for sample clean-up. The extracted drug was treated with pentafluorobenzyl bromide followed by bis(trimethylsilyl)trifluoroacetamide. The derivative was quantitatively analysed by negative-ion chemical ionization gas chromatography-mass spectrometry. The lower limit of quantitation was 50 pg/ml when 1 ml of human plasma was used. The plasma concentration of ciprostene in a dog treated with ciprostene at 2.5 micrograms/kg was determined successfully by this method.

Pharmacokinetics of rioprostil in human plasma as assayed by combined capillary gas chromatography-negative ion chemical ionization mass spectrometry.

To investigate the pharmacokinetics of rioprostil in man an assay is developed to analyse levels of rioprostil in plasma. After extraction and purification by solid-phase cartridges rioprostil is measured by negative ion chemical ionization mass spectrometry using a deuterated internal standard. The method is validated by a recovery experiment. Levels of rioprostil in the plasma of four volunteers following a single oral dose of 600 micrograms rioprostil are found as always below 100 pg/ml. The data presented here suggest that rioprostil is transformed rapidly in man to its more polar metabolites.

The role of the blood in metabolism of prostaglandin E1 in the cat lung.

We found that when 15-keto-PGE1 was added to cat blood, it was converted to 13, 14-dihydro-15-keto-PGE1 (dihydro-keto-PGE1) by a NADH-dependent enzyme associated with some formed element(s) in the blood. When PGE1 was injected into the pulmonary artery of blood-perfused lungs, the only metabolite detectable in the pulmonary venous blood was the dihydro-keto-PGE1. However, when the lungs were perfused with an artificial perfusate containing no blood cells, a small amount of 15-keto-PGE1 was detected in the venous effluent. Therefore it would appear that a blood-borne delta13 reductase was partially responsible for the conversion of PGE1 to dihydro-keto-PGE1 on passage through blood-perfused cat lungs.