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

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.

Utility of non-human primates in drug development: Comparison of non-human primate and human drug-metabolizing cytochrome P450 enzymes

“…During drug development, it is important to predict how the pharmacokinetics of drug candidates will change in older patients to reduce related risks. Cynomolgus monkeys (aged 16 years) may be a suitable animal model to predict the age-related alterations of pharmacokinetics and physiological parameters in humans, because age-related alterations of physiological parameters or reduced hepatic clearances of some human P450 substrates in cynomolgus monkeys are in agreement with clinical observations in humans [18,37], as briefly indicated in Table 4. At least, cynomolgus monkey P450 2C19-and P450 3A-mediated drug clearances showed similar age-related decreases in hepatic clearance values to those of humans (Table 4).…”

Diphenhydramine exposure in dogs: 621 cases (2008–2013)

“…Development of tachycardia and hyperthermia following diphenhydramine administration likely reflects the antagonistic effect of the drug on peripheral muscarinic cholinergic receptors. 22,26 For dogs suspected of consuming diphenhydramine but the exact time of ingestion is unknown, we recommend that they be monitored for clinical signs of toxicosis for at least 4 to 6 hours. 12 Because diphenhydramine inhibits presynaptic serotonin reuptake, serotonin syndromelike signs such as myoclonus, hyperthermia, and hyperreflexia have also been described in humans who receive extreme overdoses of the drug.…”

The pharmacokinetics of DPH after the administration of a single intravenous or intramuscular dose in healthy dogs

“…Higher Cl values have been reported after the i.v. dose of 0.2 mg/kg in 2‐year‐old dogs (33.8 mL/kg/min) and in 11‐year‐old dogs (70.1 mL/kg/min), in another study (Koyanagi et al ., ). In the latter study, differences in clearance between the two age groups were attributed to decreased hepatic function in older individuals from lower hepatic blood flow and hepatic metabolism, and longer T 1/2 , due to a decrease in hepatic extraction ratio (Meredith et al ., ; Simons et al ., ).…”

“…In a recent study, the Vd at steady‐state after the dose of 0.2 mg/kg, i.v., was 10.5–12.1 L/kg (Koyanagi et al ., ). The high Vd suggests that DPH distributes extensively in the body tissues, probably because of its high lipid solubility (logP o/w = 3.27) (Hansch et al ., ), despite moderate–high plasma protein binding of 76–98% reported in dogs and other species (Albert et al ., ; Spector et al ., ; Yoo et al ., ; Koyanagi et al ., ). High Vd values after i.v.…”