title: Evaluation of Acid Tolerance of Drugs Using Rats and Dogs Controlled for Gastric Acid Secretion.
abstract: We attempted to establish animal models to evaluate the effects of drug degradation in the stomach on oral bioavailability. In addition, we assessed the utilization of animal studies in determining the need for enteric-coated formulations. In order to control the gastric pH in rats and dogs, appropriate dosing conditions were investigated using pentagastrin and rabeprazole, which stimulate and inhibit gastric acid secretion. Using animals controlled for gastric acid secretion, the area under curve (AUC) ratios (AUC with rabeprazole/AUC with pentagastrin) of all compounds unstable under acidic conditions were evaluated. The AUC ratios of omeprazole and erythromycin, which are administered orally to humans, as enteric-coated tablets, were greater than 1.9 in the rats and dogs controlled for gastric acid secretion. On the contrary, the AUC ratios of clarithromycin, azithromycin, and etoposide (commercially available as a standard immediate-release form) were less than 1.3 each. In conclusion, in vivo models using rats and dogs were optimized to evaluate the effects of gastric acid on the oral bioavailability of drugs, and demonstrated that in vivo models can lead to a better understanding of the oral bioavailability, with respect to the formulation development.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kosugi
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Sano
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Atsutoshi
authors.initials: A
authors.lastname: Furuta
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Igari
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujioka
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amano
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism*; D005745:Gastric Acidity Determination; D005746:Gastric Emptying; D006863:Hydrogen-Ion Concentration; D008297:Male; D010418:Pentagastrin / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D051381:Rats; D013608:Tablets, Enteric-Coated
chemical_list: D004364:Pharmaceutical Preparations; D054328:Proton Pump Inhibitors; D013608:Tablets, Enteric-Coated; D010418:Pentagastrin
keywords: acid tolerance; enteric coating; formulation; gastric acid secretion; gastric pH; oral bioavailability; pentagastrin; pharmacokinetics; stability