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J F Tjia

Publications and source records attributed to J F Tjia.

25 records · Page 2Linked to original sources
PubMed1988

In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines.

1. A number of compounds have been examined for their ability to inhibit tolbutamide hydroxylase activity in human liver microsomes (control value at a substrate concentration of 150 microM being 0.27 +/- 0.12 nmol min-1 mg-1 protein; mean +/- s.d.; n = 7). 2. IC50 (concentration of inhibitor producing 50% inhibition) values were determined for a range of sulphonamides, imidazoles and aminoquinoline compounds. The most potent inhibition was evident with the 1-substituted imidazole antimycotic drugs ketoconazole, clotrimazole and miconazole and the sulphonamide sulphaphenazole (IC50 values of 16.5, 2.5, 0.85 and 0.5 microM respectively). A number of compounds showed little or no inhibition of tolbutamide hydroxylase as judged by an IC50 of greater than or equal to 500 microM. 3. The Km value for tolbutamide hydroxylase was 125 microM and Vmax, 0.44 nmol min-1 mg-1 protein. All the substituted imidazoles examined in kinetic studies 1v vs 1s, Line-weaver-Burk plots) produced either non-competitive or mixed inhibition. The sulphonamides exhibited competitive inhibition, the Ki for sulphaphenazole being 0.22 microM. Primaquine showed mixed inhibition. Dixon plots confirmed the type of inhibition produced. 4. Although the competitive inhibition between some sulphonamides and tolbutamide is consistent with metabolism by the same isozyme of cytochrome P-450 it does not prove it and further studies with purified enzymes will be necessary to confirm this.

Adolescent↗
PubMed1987

Single dose primaquine has no effect on paracetamol clearance.

The kinetics of paracetamol and the formation of metabolites were evaluated in 6 healthy volunteers before and during concomitant administration of a single dose (45 mg) of primaquine. There was no effect of the antimalarial drug on either conjugation (to paracetamol glucuronide and paracetamol sulphate) or oxidation (as judged by the presence of paracetamol cysteine and paracetamol mercapturate) pathways. Although primaquine inhibits certain oxidative metabolism (e.g. of antipyrine) it has no effect, in therapeutic doses, on paracetamol metabolism.

Acetaminophen↗
PubMed1985

Inhibition of tolbutamide metabolism by substituted imidazole drugs in vivo: evidence for a structure-activity relationship.

Tolbutamide has been used as a model drug for an examination of the effects of eleven substituted imidazole compounds on hepatic metabolism in vivo. The 1-substituted compounds 1-methylimidazole, miconazole, clotrimazole and ketoconazole produced marked alterations in tolbutamide kinetics (increased half-life, decreased clearance). However, if there was substitution in the 2- position, irrespective of a substituent on N-1, then the compound did not appear to inhibit metabolism (e.g. 2-methylimidazole, 1,2-dimethylimidazole, methimazole, metronidazole). The 4- substituted compounds, 4-methylimidazole and cimetidine were inhibitors. A structure-activity relationship for the inhibitory actions of the substituted imidazoles is thus evident in vivo.

Animals↗
PubMed1985

The effect of some benzimidazoles on the disposition of antipyrine and tolbutamide from the rat isolated perfused liver.

The anthelmintic benzimidazoles, mebendazole, albendazole and flubendazole have been screened for any propensity to alter the disposition of antipyrine and tolbutamide in the rat isolated perfused liver preparation. The benzimidazoles were added as a 2.5 mg bolus dose into the perfusate reservoir 5 min before the administration of either antipyrine or tolbutamide. Neither mebendazole or albendazole produced any significant effect on the pharmacokinetics of either of the substrate drugs. In contrast, flubendazole significantly decreased the clearance of antipyrine (by 40%) indicating inhibition of mixed function oxidase activity. However, flubendazole did not alter the disposition of tolbutamide. The results suggest that not all benzimidazoles inhibit hepatic drug metabolizing enzymes and that different forms of cytochrome P-450 are involved in the metabolism of antipyrine and tolbutamide.

Animals↗
PubMed1984

Tolbutamide as a model drug for the study of enzyme induction and enzyme inhibition in the rat.

The effects of various drugs on the pharmacokinetics of tolbutamide have been examined in the rat. Phenobarbitone pretreatment caused a significant decrease in half life and area under the curve (AUC) and a significant increase in clearance and volume of distribution (Vd). Acute administration of primaquine significantly increased half life and AUC and decreased clearance. In contrast, the related animoquinolone chloroquine, was without effect. Acute administration of cimetidine produced similar changes to primaquine but of lesser magnitude. Formation of the major metabolite hydroxytolbutamide, was markedly enhanced by phenobarbitone and reduced by primaquine and cimetidine. We conclude that due to its single pathway of metabolism, tolbutamide is a good substrate to use when examining pharmacokinetic interactions involving hepatic enzyme induction and inhibition.

Animals↗