Absorption of prostaglandins by the intestine and vagina of the rat

Abstract

An in situ method was used to determine the rate of absorption of prostaglandins ★★ E 2, F 2α, 15-methyl F 2α and 15-methyl F 2α methyl ester from the small intestine of the rat. Prostaglandin E 2 disappeared from the lumen with a t 1 2 of 37 min. From 2–3 % of the radioactivity of the dose was recovered in the blood at 30–60 min, but the compound was extensively metabolized, and intact prostaglandin E 2 did not exceed 0.04–0.08% of the dose. Absorption of the more polar prostaglandin F 2α and 15-methylprostaglandin F 2α proceeded at a slower rate with a t 1 2 of 60–70 min. Radioactivity in the serum at 30–60 min did not exceed 2 % of the dose for those animals given prostaglandin F 2α or 0.8% of the dose for those animals given 15-methylprostaglandin F 2α. A rapid, initial disappearance of 15-methylprostaglandin F 2α methyl ester from the small intestine was observed, followed by a second, much slower rate of absorption. The rapid phase of the absorption was extended at high dosages and resulted in blood levels of radioactivity up to 7 % of the dose when 40 mg/kg were given. These results correlated with the rate of hydrolysis of the methyl ester in the lumen of the intestine which was slower at higher doses. Little or no methyl ester was detected in serum or intestinal tissue, but up to 1 .8 % of the dose of intact 15-methylprostaglandin F 2α was estimated to be in the serum at 30 min. Additional experiments showed that 15-methylprostaglandin F 2α methyl ester also was absorbed through the large intestine and the vagina. In each case, 15-methylprostaglandin F 2α was found in the blood. Metabolites consisted of more polar acids and a component which migrated close to 15-methylprostaglandin F 2α on thinlyer chromatograms. The extent of metabolism of 15-methylprostaglandin F 2α methyl ester by the liver was determined in a perfusion experiment. The methyl ester was hydrolyzed within 1 min, and the free acid was taken up almost quantitatively by the circulating prostaglandins E and F occurs via 15-dehydrogenation, our results indicate that the liver is capable of extensively degrading the compounds to more polar meta-boites. Further evidence on this point comes from a liver perfusion experiment carried out as described above but with [5,6- 3H 2]prostaglandin E 1. By 60 min, over 50% of the radioactivity in plasma was recovered in volatile form 3H 2O and 17% remained in the aqueous phase, indicating extensive carboxyl sidechain cleavage. (An additional 10.3 % chromatographed as prostaglandin E 1). Dawson et al. 29 have reached similar conclusions. These observations may explain the lack of any prolongation in cardiovascular responses in vivo by the 15-methyl analogs over that observed with the parent compounds 17 but does not offer an explanation for the enhanced antifertility activity of the analogs in hamsters, monkeys and humans 17,30–32. It would, of course, be possible to speculate that cardiovascular activity relies on continuing levels of compound in the circulation while duration of antifertility activity is controlled by the local action of 15-hydroxyprostaglandin dehydrogenase on prostaglandins at target tissues 17. Uterine tissue was found to contain relatively little dehydrogenase 33, but high levels have been reported in human placenta 34. A number of orally active drugs have been found to have t 1 2 values between 8 and 50 min using the present technique 18. Therefore, barriers to successful oral dosage forms for the prostaglandins do not lie in their rate of uptake, but rather in the extensive metabolism occurring during absorption. The extremely low amounts of intact prostaglandin E 2 that survived intestinal transport, and the detection of a metabolite in the lumen of the intestine as well as in serum with the correct R F for the 15-keto compound suggest that the 15-dehydrogenation reaction poses the major metabolic block to successful intestinal absorption. In addition, dehydrogenase activity was readily detected in intestinal washes (unpublished observations). It is not possible to completely evaluate the relative role of the various degradative pathways in the intestine versus those in liver or lung during absorption on the basis of the present experiments. However, it is apparent that appreciable blood levels of intact drug could be obtained during intestinal absorption by employing an analog in which only the action of the dehydrogenase was blocked.