  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.
