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Ketamine is widely used in veterinary medicine and in medicine. Ketamine ismetabolized to its active metabolite norketamine principally by liver CYP3A.Drug metabolism alterations during aging have severe consequences particularlyin anesthesiology and very few studies on older animals were conducted forketamine. The objective of the present study is to assess the influence ofaging on CYP3A metabolism of ketamine. Liver S9 fractions from 3, 6, 12 and 18month old male Sprague Dawley rats were prepared and Michaelis-Mentenparameters were determined for primary metabolic pathways. The derived maximumenzyme velocity (i.e. Vmax) suggests a rapid saturation of the CYP3A enzymeactive sites in liver S9 fractions of 18-month old rats. Observed Vmax forLiver S9 fractions from 3, 6 and 12 month old male Sprague Dawley rats were2.39 (+-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 whencomparing Liver S9 fractions from 18 month old male Sprague Dawley rats withLiver S9 fractions from younger rats. Our results suggest that rat CYP3A enzymeundergoes conformational changes with age particularly in our geriatric group(e.g. 18 month rats) leading significant decrease in the rate of formation ofnorketamine. Moreover, our results strongly suggest a severe impairment ofCYP3A ketamine mediated metabolism.

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