CYP3A4-mediated oxidation of lisofylline to lisofylline 4,5-diol in human liver microsomes

Journal of Pharmaceutical Sciences
H S Shin, J T Slattery

Abstract

The cytochrome P450s responsible for the conversion of lisofylline, a drug being developed to prevent the complications of high-dose chemotherapy, to lisofylline 4,5-diol, one of two principal metabolites in human liver microsomes, were evaluated. Lisofylline diol formation in microsomes prepared from five adult human livers was biphasic, with respective Km values of 0.0230+/-0.015 and 4.23+/-2.8 mM (mean +/- SD) and respective Vmax values of 0.0565+/-0.052 and 0.429+/-0.15 nmol/min/mg of protein. Through studies with isoform selective chemical inhibitors, CYP3A4 was implicated as the low Km enzyme from 89.0+/-11.2% inhibition of lisofylline 4,5-diol formation by troleandomycin at 50 microM substrate and CYP2A6 was implicated as the high Km enzyme. The formation of lisofylline 4,5-diol by these enzymes was confirmed with cDNA-expressed human CYP3A4 and CYP2A6.

References

Jan 1, 1994·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·D LandmanS S Sathe
Apr 22, 1993·Biochemical Pharmacology·K E ThummelJ T Slattery

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Citations

May 9, 2002·Drug Metabolism Reviews·Slobodan Rendic
Jul 19, 2002·Chirality·Marie NicklassonPeter Höglund
Dec 14, 2004·Biochemical Pharmacology·Zandong YangJerry L Nadler
Feb 11, 2015·European Journal of Drug Metabolism and Pharmacokinetics·Elżbieta WyskaKatarzyna Przejczowska-Pomierny
Dec 12, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Artur ŚwierczekJacek Mlynarski
May 3, 2011·Journal of the American Chemical Society·Aaron T LarsenKarine Auclair

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