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  • Age-related pharmacokinetic changes of acetaminophen, antipyrine, diazepam, diphenhydramine, and ofloxacin in male cynomolgus monkeys and beagle dogs.

Age-related pharmacokinetic changes of acetaminophen, antipyrine, diazepam, diphenhydramine, and ofloxacin in male cynomolgus monkeys and beagle dogs.

Xenobiotica; the fate of foreign compounds in biological systems (2014-03-22)
Takashi Koyanagi, Yoshiyuki Yamaura, Koji Yano, Soonih Kim, Hiroshi Yamazaki
ABSTRACT

1. The pharmacokinetics of acetaminophen (marker of gastric emptying), antipyrine (marker of hepatic metabolic activity and total body water), diazepam (lipophilic and highly distributed), diphenhydramine (hepatic blood flow-limited and alpha-1 acid glycoprotein bound) and ofloxacin (renally eliminated) were evaluated in cynomolgus monkeys (3-18 years old) and beagle dogs (2-11 years old) as models in elderly persons. 2. Gastric pH fluctuated with aging in monkeys and dogs. The concentration of alpha-1 acid glycoprotein appeared to be increased by aging. There were no age-related differences in the absorption rates of the drugs under the conditions used in the study. Total body fat increased and water decreased in monkeys, but these parameters did not change in dogs. 3. Hepatic blood flow decreased in both species, but a significant decrease of hepatic clearance was only seen in monkeys. Renal clearance decreased significantly with age in monkeys and showed a tendency to decrease in dogs. 4. Age-related alterations of physiological parameters in monkeys are in agreement with clinical observations in humans, except for the lack of a change in the plasma albumin concentration. Therefore, this study suggests that monkey might be a suitable animal model for prediction of age-related changes in pharmacokinetics in humans.

MATERIALS
Product Number
Brand
Product Description

Paracetamol, European Pharmacopoeia (EP) Reference Standard
Supelco
Acetaminophen, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Diphenhydramine hydrochloride, Pharmaceutical Secondary Standard; Certified Reference Material
Diphenhydramine hydrochloride, European Pharmacopoeia (EP) Reference Standard
Supelco
Ofloxacin, VETRANAL®, analytical standard
USP
Acetaminophen, United States Pharmacopeia (USP) Reference Standard
Supelco
Ofloxacin, Pharmaceutical Secondary Standard; Certified Reference Material
USP
Ofloxacin, United States Pharmacopeia (USP) Reference Standard
Ofloxacin, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Acetaminophen, analytical standard
Sigma-Aldrich
Ofloxacin, fluoroquinolone antibiotic
Supelco
Antipyrine, analytical standard
Sigma-Aldrich
Diazepam
Sigma-Aldrich
Acetaminophen, meets USP testing specifications, 98.0-102.0%, powder
Sigma-Aldrich
Acetaminophen, BioXtra, ≥99.0%
Supelco
Acetaminophen solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Sigma-Aldrich
Diphenhydramine hydrochloride, ≥98% (HPLC)
Supelco
Diazepam solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
USP
Diphenhydramine hydrochloride, United States Pharmacopeia (USP) Reference Standard