Kinetics of glyburide metabolism by hepatic and placental microsomes of human and baboon.
Glyburide (glibenclamide) is under investigation for treatment of gestational diabetes. Two metabolites of glyburide have been previously identified in patients, namely, 4-trans-(M1) and 3-cis-(M2) hydroxycyclohexyl glyburide. Recently, the metabolism of glyburide by microsomes of liver and placenta from humans and baboons revealed the formation of four additional metabolites: 4-cis-(M2a), 3-trans-(M3), and 2-trans-(M4) hydroxycyclohexyl glyburide, and ethyl-hydroxy glyburide (M5). The aim of this investigation was to determine the kinetics for the metabolism of glyburide by cytochrome P450 (CYP) isozymes of human and baboon placental and hepatic microsomes. The metabolism of glyburide by microsomes from the four organs revealed saturation kinetics and apparent K(m) values between 4 and 12 microM. However, the rates for formation of the metabolites varied between organs and species. M1 was the major metabolite (36% of total), formed by human hepatic microsomes with V(max) of 80+/-13 pmol mg protein(-1)min(-1), and together with M2, accounted for only 51% of the total. M5 was the major metabolite (87%) formed by human placental microsomes with V(max) of 11 pmol mg protein(-1)min(-1). In baboon liver, M5 had the highest rate of formation (V(max) 135+/-32 pmol mg protein(-1)min(-1), 39% of total), and in its placenta, was M4 (V(max) 0.7+/-0.1 pmol mg protein(-1)min(-1), 65%). The activity of human and baboon hepatic microsomes in metabolizing glyburide was similar, but the activity of human and baboon placental microsomes was 7% and 0.3% of their respective hepatic microsomes. The data obtained suggest that more than 1 CYP isozyme is responsible for catalyzing the hydroxylation of glyburide.
Zharikova
Olga L
OL
Department of Obstetrics & Gynecology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0587, USA.
Ravindran
Selvan
S
Nanovskaya
Tatiana N
TN
Hill
Ronald A
RA
Hankins
Gary D V
GD
Ahmed
Mahmoud S
MS
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005905:Glyburide / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D015394:Molecular Structure; D010215:Papio; D010920:Placenta / Q000187:drug effects / Q000201:enzymology*; D011247:Pregnancy; D013045:Species Specificity
D007004:Hypoglycemic Agents; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D005905:Glyburide