Hiroaki Mizuta

Relationship between the phasic period of interdigestive migrating contraction and the systemic bioavailability of acetaminophen in dogs

The relationships of the phasic period of interdigestive migrating contraction to gastrointestinal (GI) transit of drugs and their oral absorption were investigated in mongrel dogs by simultaneous oral dosing of acetaminophen (AAP) and salicylazosulfapyridine (SASP) at the starting points of the phase I and phase III periods of gastric contractions. Strain-gauge force transducers were surgically sutured onto the serosa of the GI tracts in the dogs to measure the interdigestive migrating contractions. The mean absorption time of AAP and the time for the first appearance of sulfapyridine (a bacterial metabolite of SASP in the colon) in plasma were used as the indices of gastric emptying time (GET) and small intestinal transit time (SITT), respectively. In individual dogs, the GET and the SITT at phase I showed a clear delay in comparison with those at phase III. For AAP used as a marker compound here, the systemic bioavailability after oral dosing to intact beagle dogs at doses of 3, 10, and 20 mg/kg was about 55, 63, and 79%, suggesting that AAP undergoes a non-linear hepatic clearance. At a dose of AAP 20 mg/kg, the systemic bioavailability of AAP was 100% in the case of dosing at phase III, but was reduced by half when dosing at phase I. These results indicate that, in oral dosing, the transit of drugs through the GI tract was clearly affected by the phases of gastric contractions. Phasic GI motility is thus concluded to be a cause for the inter- and intraindividual variations in the systemic bioavailability of drugs such as AAP that undergo a non-linear hepatic clearance, as a result of either gradual or rapid transport of drugs to enzymes on their first pass through the liver.

[Improvement of gastrointestinal absorption of 2-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin- 1-yl]ethyl acetate, a new non-steroidal anti-inflammatory agent].

The effects of triglycerides on the gastrointestinal absorption of 2-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-1- yl]ethyl acetate (1) were investigated in dogs. The enhancing abilities of the triglycerides on the absorption of 1 were demonstrated as in the order of trilinolein greater than triolein greater than tristearin greater than tripalmitin. Among the series of fatty acids and monoglycerides, namely, digestive products of triglycerides by pancreatic lipase, linoleic acid and monolinolein showed the most potent solubilizing activities of 1 in a solution of bile salt. The incorporation of 1 into mixed micelle formed by lipids and bile salts was presumed to play an important role in the accelerated absorption of 1 after ingestion of triglycerides. On the basis of these findings, an emulsion containing 1 was prepared with soybean oil. The emulsion exhibited a remarkable improvement of the absorption of 1 compared to a suspension of the drug in methylcellulose solution.

[Effects of bile and meal on the gastrointestinal absorption of 2-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin- 1-yl]ethyl acetate, a new non-steroidal anti-inflammatory agent].

The effects of bile and meal on the gastrointestinal absorption of 2-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin - 1-yl]ethyl acetate (1), were investigated in rats and dogs. Compound 1 was lipophilic and soluble in bile, but extremely insoluble in water. The important role of bile in the dissolution step in the absorption process of 1 was confirmed on the in situ absorption study with rats. Oral absorption of 1 was insufficient and showed a marked individual difference in fasting dogs. When the same compound was administered after ingestion of a meal, the absorption increased with decreasing scatter. Three kinds of meals had different potencies to enhance the bio-availability of 1 in the order of lard greater than mashed potatoes greater than skimmed milk. The absorption behavior of 1 reflected small intestinal transit time and the stimulated bile output after ingestion of meal.