Disposition of the enantiomers of cromakalim in rat and cynomolgus monkey.

1. Disposition of the 3R,4S(+) and 3S,4R(-) enantiomers of the racemic antihypertensive drug cromakalim has been studied in rats and cynomolgus monkeys using the 14C-drug labelled in either the 3R,4S(+) or the 3S,4R(-) enantiomer. 2. After oral administration to rat, blood concentrations of the 3R,4S(+) enantiomer were up to fourfold higher than those of the 3S,4R(-) enantiomer. Metabolism of the former was not as extensive as that of the latter and consequently plasma and urinary radiometabolite patterns were quantitatively different. 3. In contrast to rat, there were much greater differences in the disposition of the two enantiomers following oral administration of cromakalim to the cynomolgus monkey. Plasma concentrations of the 3R,4S(+) enantiomer were approximately 100 x those of the 3S,4R(-) enantiomer and the rate of urinary 14C elimination for the 3R,4S(+) enantiomer was much faster than that for the 3S,4R(-) enantiomer. Plasma and urinary radiometabolite patterns were very different for the two isomers. Metabolic end products of the 3R,4S(+) enantiomer were predominantly phase I metabolites whereas the 3S,4R(-) enantiomer was almost entirely metabolized by glucuronidation. 4. A study of the racemic drug alone would have led to a misunderstanding of the fate of the compound in these species.

A novel technique for assessment of biliary secretion and enterohepatic circulation in the unrestrained conscious rat.

1. A technique is described for the continuous collection of bile, for long periods, from unrestrained conscious rats housed in standard glass metabolism cages. 2. Bile is collected in cooled vessels outside the cage through a cannula which is exteriorized at the back of the neck and is protected from damage by an outer covering. 3. A minimum recovery period of three days is allowed after the operation, by which time liver function and intestinal motility are normal. 4. An extension of the technique can be used to assess enterohepatic circulation.

The disposition and metabolism of the synthetic prostaglandin fluprostenol (ICI 81,008) in the horse.

1. Following single intramuscular doses of [14C]fluprostenol (0.5--2.4 micrograms/kg) to three female horses and to three gelded male horses, radioactivity was present in the plasma within 5 min; peak concn. (0.32--1.30 ng/ml fluprostenol equiv.) occurred 5 to 90 min after injection. Radioactivity was still present in the plasma of the females after three days. About 88% of fluprostenol is bound to plasma proteins. 2. Radioactivity was present in the parotid saliva of the gelded male horses within 10 min. Peak concn. (45--91 pg/ml fluprostenol equiv.) occurred from 5 min to 1 h after injection. Saliva : plasma concn. ratios varied inversely with saliva flow rate and limiting ratios were 0.33 and 0.41 for the combined results of two experiments on each of two male horses; the calculated value is 0.46 Chromatography indicated that the majority of plasma and saliva radioactivity was [14C]fluprostenol. 3. Excretion of radioactivity in the urine was rapid and virtually complete 12 h after dosing. The total radioactivity excreted in urine by the female horses was 45% of the dose (96 h) and by the gelded male horses 53% (30 h). About 30% of the radioactivity present in the urines was unchanged fluprostenol. 4. Faecal excretion, which was substantially complete after 2 days, accounted for 32% of the radioactivity administered to the female horses. 5. Tissue conc. of radioactivity in the female horses at four days were below the limits of detection (90 pg/g), but 0.2--0.9% of the dose was detected at the site of injection.