title: Inhibition of tolbutamide metabolism by antimalarial drugs.
abstract: The effects of mefloquine (MQ), the combination of MQ with sulfadoxine-pyrimethamine (MSP), sulfadoxine (S), pyrimethamine (P) quinine (Q) and quinidine (Qd) on in vitro hepatic metabolism has been studied using tolbutamide as a substrate. The hydroxylation of tolbutamide was determined in the presence of variable concentrations of each compound. Tolbutamide hydroxylase activity in control microsomes was 0.20 +/- 0.13 nmole/min/mg microsomal protein at a substrate concentration of 150 microM. All compounds studied inhibited tolbutamide metabolism as shown by a decrease in 4-hydroxytolbutamide formation. The order of potency of the inhibitors was MSP greater than S greater than MQ greater than Q greater than Qd greater than P. MQ, MSP, S, Q, and Qd were examined in detail for the type of inhibition. MQ and Qd were non-competitive inhibitors, whereas MSP and S were competitive inhibitors and Q was an uncompetitive inhibitor of tolbutamide 4-hydroxylation. These data provide more information on the inhibitory potential of some antimalarial drugs on microsomal enzymes in human liver. S has been shown to be a potent inhibitor in vitro and this finding possibly explains the longer T 1/2 and MRT of MQ when co-administered with S in healthy volunteers. Further studies in man should be attempted in order to understand the clinical relevance of the inhibitory potential of the antimalarial drugs.
authors.affiliation: Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Thailand.
authors.forename: J
authors.initials: J
authors.lastname: Karbwang
authors.forename: D J
authors.initials: DJ
authors.lastname: Back
authors.forename: D
authors.initials: D
authors.lastname: Bunnag
authors.forename: A M
authors.initials: AM
authors.lastname: Breckenridge
mesh_terms: D000328:Adult; D000368:Aged; D000962:Antimalarials / Q000493:pharmacokinetics*; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases; D014044:Tolbutamide / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D000962:Antimalarials; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D014044:Tolbutamide; C031014:hydroxymethyltolbutamide; D000096926:Benzenesulfonamides