CYP3A Mediated Ketamine Metabolism is Severely Impaired in Liver S9 Fractions from Aging Sprague Dawley Rats

TL;DR

This study demonstrates that aging significantly impairs CYP3A enzyme activity in rat liver, leading to reduced ketamine metabolism, which has important implications for anesthetic dosing in older animals.

Contribution

It provides the first detailed analysis of age-related changes in CYP3A-mediated ketamine metabolism in rats, highlighting conformational enzyme changes with aging.

Findings

Severe reduction in Vmax of CYP3A in 18-month-old rats.

6-7 fold increase in Km indicating decreased enzyme affinity with age.

Impaired ketamine metabolism in aged rat liver S9 fractions.

Abstract

Ketamine is widely used in veterinary medicine and in medicine. Ketamine is metabolized to its active metabolite norketamine principally by liver CYP3A. Drug metabolism alterations during aging have severe consequences particularly in anesthesiology and very few studies on older animals were conducted for ketamine. The objective of the present study is to assess the influence of aging on CYP3A metabolism of ketamine. Liver S9 fractions from 3, 6, 12 and 18 month old male Sprague Dawley rats were prepared and Michaelis-Menten parameters were determined for primary metabolic pathways. The derived maximum enzyme velocity (i.e. Vmax) suggests a rapid saturation of the CYP3A enzyme active sites in liver S9 fractions of 18-month old rats. Observed Vmax for Liver S9 fractions from 3, 6 and 12 month old male Sprague Dawley rats were 2.39 (+-0.23), 2.61 (+-0.18), and 2.07 (+-0.07) respectively compared to 0.68 (+-0.02) for Liver S9 fractions from 18 month old male Sprague Dawley rats. Interestingly, we observed a 6 to 7 fold change in the derived Km when comparing Liver S9 fractions from 18 month old male Sprague Dawley rats with Liver S9 fractions from younger rats. Our results suggest that rat CYP3A enzyme undergoes conformational changes with age particularly in our geriatric group (e.g. 18 month rats) leading significant decrease in the rate of formation of norketamine. Moreover, our results strongly suggest a severe impairment of CYP3A ketamine mediated metabolism.