Inhibition of tolbutamide metabolism by antimalarial drugs.
Southeast Asian J Trop Med Public Health
;
1988 Jun; 19(2): 235-41
Article
in English
| IMSEAR
| ID: sea-32006
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.
Full text:
Available
Index:
IMSEAR (South-East Asia)
Main subject:
Tolbutamide
/
Aged
/
Humans
/
Male
/
Microsomes, Liver
/
Child, Preschool
/
Adult
/
Cytochrome P-450 Enzyme System
/
Mixed Function Oxygenases
/
Hydroxylation
Language:
English
Journal:
Southeast Asian J Trop Med Public Health
Year:
1988
Type:
Article
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