Enhanced cholesterol reduction by simvastatin in diltiazem‐treated patients

Yeo, Rowland; Yeo,; Ramsay,

doi:10.1046/j.1365-2125.1999.00066.x

Cited by 27 publications

(2 citation statements)

References 20 publications

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“…This may have important clinical implications for the cholesterol‐lowering response to simvastatin in individuals who are also taking verapamil or diltiazem. The results of a retrospective study reported previously by our group demonstrated that there was enhanced cholesterol reduction in patients who were taking simvastatin and diltiazem concurrently, and the interindividual variability in cholesterol‐lowering response to simvastatin was significantly lower for patients taking diltiazem than for patients not taking diltiazem [24]. To date, no studies have been reported regarding the effect of verapamil on the cholesterol‐lowering response to simvastatin.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes

Yeo

2001

Brit J Clinical Pharma

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Aims To determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation parameters with those reported previously for mibefradil. Methods Simvastatin metabolism was investigated in human liver microsomes in the presence and absence of verapamil or diltiazem (0.1±250 mM). Kinetics of CYP3A4 inactivation by verapamil and diltiazem were determined using testosterone as the substrate. Results When verapamil was coincubated with simvastatin, IC 50 values ranged from 23 to 26 mM for all major metabolites. The IC 50 values ranged from 4.8 to 5.6 mM on preincubation of verapamil for 30 min in the presence of an NADPH-generating system. Corresponding IC 50 values for diltiazem ranged from110±127 mM and from 21±27 mM, respectively. Verapamil and diltiazem inhibited testosterone 6b-hydroxylation in a time-and concentration-dependent manner, key features of mechanismbased inactivation. Values for the inactivation parameters k inact and K I were 0.15t0.04 min x1 (mean t s.d.) and 2.9t0.6 mM, respectively, for verapamil and 0.07t0.01 min x1 and 3.3t1.5 mM, respectively, for diltiazem. ConclusionsThe IC 50 values for coincubation of verapamil and diltiazem were 46-and 220-fold higher, respectively, than those reported previously for mibefradil, and 16-and 71-fold higher, respectively, for preincubation. Thus, the results of this study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism-based inhibitors of CYP3A4 and therefore may still cause signi®cant inhibition of simvastatin metabolism in vivo during chronic therapy.

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Section: Discussionmentioning

confidence: 99%

Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes

Yeo

2001

Brit J Clinical Pharma

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“…Coadministration of simvastatin with CYP3A inhibitors results in elevated plasma concentrations of the active simvastatin acid, which in turn is expected to elevate concentrations in tissues that correspond to sites of beneficial and unwanted effects. Rowland et al 47 demonstrated that the cholesterol‐lowering response to simvastatin was significantly greater (about 30%) in patients concomitantly receiving diltiazem. The incidence of simvastatin‐induced myopathy is low but may be significantly greater in patients treated with diltiazem.…”

Section: Discussionmentioning

confidence: 99%