Abstract:Aims Our aim was to investigate the effects of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide, a novel short-acting antidiabetic drug. Methods In a randomized crossover study with two phases, 10 healthy volunteers took 600 mg rifampicin or placebo orally once daily for 5 days. On day 6 of both phases, they ingested a single 60 mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 7 h postdose. Results Rifampicin decreased the mean AUC(0,7 h)… Show more
“…It has been shown that the magnitude of other pharmacokinetic interactions involving nateglinide are generally smaller than those affecting other antidiabetic drugs. For example, rifampicin at 600 mg daily for 5 days decreased the AUC(0, •) of nateglinide by only 22% [54], whereas the same treatment caused a 57% decrease in the AUC(0, •) of repaglinide [55]. Similarly, fluconazole given at 200 mg (first dose 400 mg) daily for 4 days increased the AUC(0, •) of nateglinide by 48% [21] and that of glimepiride by 138% [16].…”
Background and aimsGemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration-time curve [AUC(0, • )] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro , gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4.
MethodsIn a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h.
ResultsDuring the gemfibrozil-itraconazole phase, the AUC(0, • ) and C max of nateglinide were 47% (range 23-74%; P < 0.0001) and 30% (range -8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the t max and t 1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole.
ConclusionsThe combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.
“…It has been shown that the magnitude of other pharmacokinetic interactions involving nateglinide are generally smaller than those affecting other antidiabetic drugs. For example, rifampicin at 600 mg daily for 5 days decreased the AUC(0, •) of nateglinide by only 22% [54], whereas the same treatment caused a 57% decrease in the AUC(0, •) of repaglinide [55]. Similarly, fluconazole given at 200 mg (first dose 400 mg) daily for 4 days increased the AUC(0, •) of nateglinide by 48% [21] and that of glimepiride by 138% [16].…”
Background and aimsGemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration-time curve [AUC(0, • )] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro , gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4.
MethodsIn a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h.
ResultsDuring the gemfibrozil-itraconazole phase, the AUC(0, • ) and C max of nateglinide were 47% (range 23-74%; P < 0.0001) and 30% (range -8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the t max and t 1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole.
ConclusionsThe combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.
“…Rosiglitazone is metabolised largely by CYP2C8, and rifampicin decreases concentrations of rosiglitazone by 54–65% and of the related drug pioglitazone by 54% 95–97. Nateglinide, a short-acting insulin secretagogue given to prevent postprandial hyperglycaemia, is metabolised by oxidative bio transformation, with involvement from CYP2C9 and CYP3A4; its area under the curve is reduced by only 24% with no appreciable glycaemic effect when given with rifampicin 98. Repaglinide, another related drug, had an area under the curve that was decreased by 31–57% when given with rifampicin, although its glucose-lowering effect was reduced in one study and unchanged in another 99,100.…”
Section: Pharmacological Issues In the Co-management Of Diabetes Mellmentioning
The link between diabetes mellitus and tuberculosis has been recognised for centuries. In recent decades, tuberculosis incidence has declined in high-income countries, but incidence remains high in countries that have high rates of infection with HIV, high prevalence of malnutrition and crowded living conditions, or poor tuberculosis control infrastructure. At the same time, diabetes mellitus prevalence is soaring globally, fuelled by obesity. There is growing evidence that diabetes mellitus is an important risk factor for tuberculosis and might affect disease presentation and treatment response. Furthermore, tuberculosis might induce glucose intolerance and worsen glycaemic control in people with diabetes. We review the epidemiology of the tuberculosis and diabetes epidemics, and provide a synopsis of the evidence for the role of diabetes mellitus in susceptibility to, clinical presentation of, and response to treatment for tuberculosis. In addition, we review potential mechanisms by which diabetes mellitus can cause tuberculosis, the effects of tuberculosis on diabetic control, and pharmacokinetic issues related to the co-management of diabetes and tuberculosis.
Summaryobjectives To review the current knowledge about tuberculosis (TB) and diabetes, assessing the implication of the global increase of diabetes for TB control and patient care.methods Systematic literature review. results Using public databases, it can be estimated that 12.6% (95% CI 9.2-17.3%) of new TB cases in the 10 countries with the highest TB burden will be attributable to TB in 2030, a relative increase of 25.5% compared to 2010. Diabetes is associated with a higher age and body weight among patients with TB, but probably not with a specific clinical presentation of TB. Rifampicin hampers glycemic control by increasing the metabolism of most oral antidiabetic drugs, while diabetes patients may have lower concentrations of anti-TB drugs. This might be one factor contributing to higher TB treatment failure rates.conclusions The global epidemic of diabetes has implications for control and treatment of TB. Prospective studies are needed to improve prevention, early detection and treatment of concomitant diabetes and TB, especially in developing countries.
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