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Species Related Differences in In Vitro Metabolism of Phenacetin, a Probe Substrate for CYP1A Enzyme, and Enzyme Kinetic Parameters of Phenacetin

Alice Varghese, Jay Savai, Nancy Pandita, and Ram Gaud
Shobhaben Pratapbhai Patel, School of Pharmacy and Technology Management, SVKM¡¯s NMIMS, Vile Parle (W), Mumbai 400056, India.
Abstract—The CYP1A P450 subfamily consists of two members, CYP1A1 and CYP1A2 in mouse, rat, dog, monkey and human. CYP1A shows a quite strong conservation among species with an identity to human higher that 80% in rat (83 and 80%, respectively for CYP1A1 and CYP1A2), mouse (83 and 80%, respectively for CYP1A1 and CYP1A2), dog (84% for CYP1A2) and monkey (95% for both CYP1A1 and CYP1A2). Drug-drug interactions may occur as a result of (a) induction of the expression of metabolizing enzymes or, (b) as a result of inhibition of enzyme activity or expression. Phenacetin is a recommended probe substrate for CYP1A for in vitro and in vivo drug interaction studies. Phenacetin has been found to be almost exclusively metabolized by CYP1A2 to its metabolite paracetamol in humans. The objective of the study was to investigate the metabolism of phenacetin to paracetamol and to determine the Km and Vmax values of phenacetin in mice, rat and pig liver microsomes. Phenacetin was metabolized to paracetamol in rat and mice liver microsomes. However, pig liver microsomes did not show metabolism of phenacetin to paracetamol, inspite of pigs reported to have CYP1A isozyme in livers. Enzyme kinetic parameters (Km and Vmax) for conversion of phenacetin in paracetamol in rat and mice liver microsomes were determined. Both rat and mice liver microsomes showed a linear formation of metabolite (paracetamol) in the concentration range of 5-160 μM and 40-100 μM of phenacetin, respectively. Km and Vmax values of phenacetin, for conversion to paracetamol, was found to be 54 μM and 0.0015 nmoles/min/mg protein, respectively in rat liver microsomes and 74 μM and 0.005 nmoles/min/mg protein, respectively in mice liver microsomes. The enzyme kinetic parameters will be useful to choose a concentration of phenacetin in vitro to carry out drug-drug interaction studies for CYP1A enzyme in rats and mice.

Index Terms—CYP1A, Liver Microsomes, Rodents, Non-rodents, Phenacetin, Km, Vmax

Cite: Alice Varghese, Jay Savai, Nancy Pandita, and Ram Gaud, "Species Related Differences in In Vitro Metabolism of Phenacetin, a Probe Substrate for CYP1A Enzyme, and Enzyme Kinetic Parameters of Phenacetin," International Journal of Pharma Medicine and Biological Sciences, Vol. 3, No. 2, pp. 21-30, April 2014.
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