Pharmacokinetics of verapamil and its metabolite norverapamil in rats with hyperlipidaemia induced by poloxamer 407

In this study, the pharmacokinetics of verapamil and its active metabolite norverapamil were evaluated following intravenous and oral administration of 10 mg/kg verapamil to rats with hyperlipidaemia (HL) induced by poloxamer 407 (HL rats). The total area under the plasma concentration time curve (AUC) of verapamil in HL rats following intravenous administration was significantly greater (by 11.2%) than in control rats due to their slower (by 11%) non-renal clearance. The oral AUC of verapamil in HL rats was also significantly greater (by 116%) compared with controls, with a larger magnitude than the data observed following intravenous administration. This may have been a result of the decreased intestinal metabolism of verapamil in HL rats. The AUC of norverapamil and AUC(norverapamil)/AUC(verapamil) ratios following intravenous and oral administration of verapamil were unchanged in HL rats. Assuming that the HL rat model qualitatively reflects similar changes in patients with HL, the findings of this study have potential therapeutic implications. Further studies in humans are required to determine whether modification of the oral verapamil dosage regimen in HL states is necessary.     

Pharmacokinetics of tolbutamide and its metabolite 4‐hydroxy tolbutamide in poloxamer 407‐induced hyperlipidemic rats

Under hyperlipidemic conditions, there are likely to be alterations in the pharmacokinetics of CYP2C11 substrates following decreased expression of CYP2C11, which is homologous to human CYP2C9. The pharmacokinetics of tolbutamide (TB) and its metabolite 4‐hydroxy tolbutamide (4‐OHTB) were evaluated as a CYP2C11 probe after intravenous and oral administration of 10 mg/kg tolbutamide to poloxamer 407‐induced hyperlipidemic rats (HL rats). Changes in the expression and metabolic activity of hepatic CYP2C11 and the plasma protein binding of tolbutamide in HL rats were also evaluated. The total area under the plasma concentration–time curve (AUC) of tolbutamide in HL rats after intravenous administration was comparable to that in controls due to their comparable non‐renal clearance (CL_NR). The free fractions of tolbutamide in plasma were comparable between the control and HL rats. The 4‐hydroxylated metabolite formation ratio (AUC_4‐OHTB/AUC_TB) in HL rats was significantly smaller than that in the control rats as a result of the reduced expression of hepatic CYP2C11 (by 15.0%) and decreased hepatic CL_int (by 28.8%) for metabolism of tolbutamide to 4‐OHTB via CYP2C11. Similar pharmacokinetic changes were observed in HL rats after oral administration of tolbutamide. These findings have potential therapeutic implications, assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Since other sulfonylureas in clinical use are substrates of CYP2C9, their hepatic CL_int changes have the potential to cause clinically relevant pharmacokinetic changes in a hyperlipidemic state. Copyright © 2014 John Wiley & Sons, Ltd.     

Effect of pioglitazone on the pharmacokinetics of verapamil and its major metabolite,norverapamil, in rats

Pioglitazone, a thiazolidinedione antidiabetic drug, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. This study investigated the effect of pioglitazone on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats, after oral administration of verapamil (9 mg/kg) in the presence or absence of pioglitazone (0.3 or 1.0 mg/kg). Pioglitazone altered verapamil pharmacokinetics compared with verapamil alone. The presence of 1.0 mg/kg of pioglitazone significantly (p < 0.05) increased the area under the plasma concentration-time curve (AUC) and the peak concentration (C(max)) of verapamil by 49.0% and 46.8%, respectively, and significantly (p < 0.05) decreased the total plasma clearance (CL/F) of verapamil by 32.8%. The metabolite-parent AUC ratio in the presence of pioglitazone (1.0 mg/kg) significantly (p < 0.05) decreased by 21.9% compared to the control group. Thus, coadministration of pioglitazone inhibited the CYP3A4-mediated metabolism of verapamil.     

Effects of naringin on the pharmacokinetics of verapamil and one of its metabolites, norverapamil, in rabbits

It was reported that verapamil is metabolized via hepatic microsomal cytochrome P450 (CYP) 3A4 and that naringin (a component of grapefruit juice) inhibits CYP3A4 in humans. Hence, after oral administration of verapamil, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of verapamil and the AUC(verapamil)/AUC(D-617 (a metabolite of verapamil)) ratio were significantly greater after oral grapefruit juice in humans. The aim of this study was to determine whether similar results could be obtained from rabbits. The pharmacokinetics of verapamil and one of its metabolites, norverapamil, were investigated after oral administration of verapamil at a dose of 9 mg/kg without or with oral naringin at a dose of 7.5 mg/kg in rabbits. With naringin, the AUC of verapamil was significantly greater (28.4 versus 18.4 microg min/ml). Although, the AUC values of norverapamil were not significantly different between groups without and with naringin, the AUC(verapamil)/AUC(norverapamil) ratio was considerably greater (1.49 versus 1.11) with naringin. The above data suggested that the metabolism of verapamil and the formation of norverapamil was inhibited by naringin possibly by inhibition of CYP3A in rabbits.     

Pharmacokinetics of clomipramine, an antidepressant, in poloxamer 407-induced hyperlipidaemic model rats

Objective This study was undertaken to investigate the effects of hyperlipidaemia on the pharmacokinetics of clomipramine, an antidepressant, particularly addressing the change of clomipramine distribution to plasma components in poloxamer 407‐induced hyperlipidaemia model rats. Methods Clomipramine pharmacokinetic studies in hyperlipidaemic rats were performed with clomipramine continuous infusion. Furthermore, clomipramine protein binding and distribution to the brain and plasma components such as lipoproteins were investigated. Key findings Mean plasma concentration of clomipramine at steady state during continuous infusion (17.5 µg/min/kg) in hyperlipidaemic rats (0.45 ± 0.01 µg/ml) was significantly higher than that in the control rats (0.30 ± 0.02 µg/ml). However, the amount of clomipramine in the brain in hyperlipidaemic rats (0.31 ± 0.06 µg/g) was dramatically lower than in the control rats (1.89 ± 0.13 µg/g). However, the plasma unbound fraction in hyperlipidaemic rats (0.98 ± 0.05%) was significantly lower than that of the control rats (6.51 ± 0.62%). Conclusions Lower distribution to the brain and lower plasma clearance of clomipramine in hyperlipidaemic rats resulted from lower plasma unbound fraction because of higher lipid‐rich protein contents in blood. Results of this study provide useful information for dosage adjustment of clomipramine in hyperlipidaemia.     

Pharmacokinetics of verapamil in diabetic rats induced by combination of high-fat diet and streptozotocin injection

1. The aim of this study was to investigate effects of type 2 diabetes on the pharmacokinetics of verapamil after intravenous administration.

2. Diabetes mellitus (DM) rats were induced by combination of high-fat diet (HFD) and streptozotocin. Plasma concentrations of verapamil in DM rats, rats fed with HFD, and control (CON) rats were measured after intravenous administration of 1?mg/kg verapamil and corresponding pharmacokinetic parameters were estimated. Area under the plasma concentration in DM rats was significantly smaller than that in CON rats.

3. In vitro microsomal study showed that intrinsic clearance of verapamil in DM rats was significantly higher than those in CON rats. Compared to CON rats, higher intrinsic clearance was also observed in HFD rats. Western blot results demonstrated higher levels of CYP3A2 in DM and HFD rats, which was in line to activity of CYP3A.

4. All the results gave a conclusion that diabetes may enhance metabolism of verapamil in rat, and the enhancement may partly result from induction of CYP3A.

     

Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite,N‐desmethylsildenafil,in rats in vitro and in vivo

Objectives It has been reported that hepatic cytochrome P450 (CYP)2C9 and CYP3A4 are responsible for the metabolism of sildenafil and formation of its metabolite, N‐desmethylsildenafil, in humans. However, in‐vivo studies in rats have not been reported. Methods Sildenafil (20 mg/kg) was administered intravenously to rats pretreated with sulfaphenazole, cimetidine, quinine hydrochloride or troleandomycin, inhibitors of CYP2C6, CYP2C11, CYP2D subfamily and CYP3A1/2, respectively. In‐vitro studies using rat liver microsomes were also performed. Key findings The area under the plasma‐concentration time curve (AUC) was increased and clearance of sildenafil decreased in rats pretreated with cimetidine or troleandomycin. The AUC ratio for N‐desmethylsildenafil (0–4 h): sildenafil (0–∞) was significantly decreased only in rats pretreated with cimetidine. Similar results were obtained in the in‐vitro study using rat liver microsomes. Conclusions Sildenafil is metabolised via hepatic CYP2C11 and 3A1/2, and N‐desmethylsildenafil is mainly formed via hepatic CYP2C11 in rats. Thus, rats could be a good model for pharmacokinetic studies of sildenafil and N‐desmethylsildenafil in humans.     

Pharmacokinetics of sildenafil and its metabolite,N-desmethylsildenafil,in rats with liver cirrhosis and diabetes mellitus,alone and in combination

1. Pharmacokinetics of sildenafil and its metabolite, N-desmethylsildenafil, in humans and rats with liver cirrhosis (LC) and diabetes mellitus (DM), alone and in combination (LCD) did not seem to be reported.

2. Sildenafil was administered intravenously (10?mg/kg) and orally (20?mg/kg) to control, LC, DM, and LCD rats. Expression of intestinal CYP isozymes in those rats was also measured.

3. In LC, DM, and LCD rats, the areas under the curve (AUCs) of intravenous sildenafil were significantly greater (by 195%, 54.2%, and 127%, respectively) than controls. In LC and LCD rats, AUCs of oral sildenafil were significantly greater (3010% and 2030%, respectively) than controls.

4. In LC, DM, and LCD rats, significantly greater AUCs of intravenous sildenafil were due to the slower hepatic extraction of sildenafil (because of decrease in the protein expression of hepatic CYP2C11 and 3A subfamily in LC and LCD rats, and CYP2C11 in DM rats). In LC and LCD rats, greater magnitude of increase in AUCs of oral sildenafil than those after the intravenous administration could be mainly due to the decrease in the intestinal extraction of sildenafil (because of decrease in the protein expression of intestinal CYP2C11 in LC and LCD rats).

     

Pharmacokinetics of 5-fluorouracil in rats with diabetes mellitus induced by streptozotocin

The pharmacokinetic parameters of 5-fluorouracil were compared after intravenous administration at a dose of 30 mg/kg to control Sprague-Dawley rats and to rats with diabetes mellitus induced by streptozotocin (DMIS). In DMIS rats, the area under the plasma concentration-time curve from time zero to time infinity (AUC) was significantly smaller (603 versus 909 microg min/ml) due to the significantly faster total body clearance (Cl; 47.8 versus 33.0 ml/min/kg). The faster Cl was due to the significantly faster renal (8.54 versus 4.02 ml/min/kg) and nonrenal (38.5 versus 28.7 ml/min/kg) clearances. In DMIS rats, the total amount of unchanged 5-fluorouracil excreted in 24 h urine was significantly greater (34.1% versus 13.0% of intravenous dose) due to the urine flow rate-dependent renal clearance of 5-fluorouracil in rats (the greater the urine flow rate, the greater the urinary excretion of 5-fluorouracil). Greater urinary excretion and a significantly smaller AUC resulted in a significantly faster Cl(r) in DMIS rats. The faster Cl(nr) in DMIS rats could be due to an increase in the expression and mRNA level of CYP1A1/2 in the rats.     

Pharmacokinetics of oltipraz in diabetic rats with liver cirrhosis

Background and purpose:

The incidence of diabetes mellitus is increased in patients with liver cirrhosis. Oltipraz is currently in trials to treat patients with liver fibrosis and cirrhosis induced by chronic hepatitis types B and C and is primarily metabolized via hepatic cytochrome P450 isozymes CYP1A1/2, 2B1/2, 2C11, 2D1 and 3A1/2 in rats. We have studied the influence of diabetes mellitus on pharmacokinetics of oltipraz and on expression of hepatic, CYP1A, 2B1/2, 2C11, 2D and 3A in rats with experimental liver cirrhosis.

Experimental approach:

Oltipraz was given intravenously (10 mg·kg⁻¹) or orally (30 mg·kg⁻¹) to rats with liver cirrhosis induced by N-dimethylnitrosamine (LC rats) or with diabetes, induced by streptozotocin (DM rats) or to rats with both liver cirrhosis and diabetes (LCD rats) and to control rats, and pharmacokinetic variables measured. Protein expression of hepatic CYP1A, 2B1/2, 2C11, 2D and 3A was measured using Western blot analysis.

Key results:

After i.v. or p.o. administration of oltipraz to LC and DM rats, the AUC was significantly greater and smaller, respectively, than that in control rats. In LCD rats, the AUC was that of LC and DM rats (partially restored towards control rats). Compared with control rats, the protein expression of hepatic CYP1A increased, that of CYP2C11 and 3A decreased, but that of CYP2B1/2 and 2D was not altered in LCD rats.

Conclusions and implications:

In rats with diabetes and liver cirrhosis, the AUC of oltipraz was partially restored towards that of control rats.     

Pharmacokinetics of phenytoin and its metabolite, 4'-HPPH, after intravenous and oral administration of phenytoin to diabetic rats induced by alloxan or streptozotocin

It has been reported that diabetic patients have an increased risk of developing epileptic convulsions compared with the non-diabetic population, and phenytoin has widely been used for neuralgia in diabetic neuropathy. It has also been reported that in both diabetic rats induced by alloxan (DMIA rats) and by streptozotocin (DMIS rats), the protein expression and mRNA level of 2C11 decreased, but in DMIS rats, the protein expression of CYP2C6 increased. Thus, the pharmacokinetics of phenytoin and 4'-HPPH were investigated after intravenous or oral administration of phenytoin at a dose of 25 mg/kg to DMIA and DMIS rats. After intravenous or oral administration of phenytoin, the AUC (or AUC(0-12 h)) values of both phenytoin and 4'-HPPH were comparable (not significantly different) between each diabetic and the respective control rats. Although the exact reason is not clear, this could have been due to opposite protein expression (and/or mRNA levels) of CYP2C6 and 2C11 in diabetic rats.     

The effect of gender on the pharmacokinetics of verapamil and norverapamil in human

The effects of gender on the pharmacokinetics of verapamil and its active metabolite, norverapamil, following single oral dose (80 mg, Isoptin) to 12 healthy male (mean age: 25.75+/-2.42 years, mean body weight: 70.59+/-9.94 kg) and 12 healthy female subjects (mean age: 24.08+/-2.84 years, mean body weight: 56.67+/-5.23 kg) were investigated in the present study. Plasma concentrations of verapamil and norverapamil were analysed using a modified high-pressure liquid chromatography method. Pharmacokinetic parameters were calculated by non-compartmental analysis for each subject. For verapamil the half-life (t1/2) and mean residence time (MRT) were significantly shorter in women than men (p<0.01 and p<0.05, respectively). For other pharmacokinetic parameters of verapamil there were no significant differences between males and females. For norverapamil, t1/2, MRT and time to reach to the maximum plasma concentration (Tmax) showed statistically significant differences between the two genders. The AUC(0-24) and AUC(0-infinity) ratios of norverapamil to verapamil were also calculated. The ratios were significantly higher in women compared with men. These observations indicate that the elimination rate of verapamil is faster in women than men which may be attributed to the higher activity of CYP3A4 or lower activity of P-glycoprotein in women compared with men. A contribution of both factors in the appearance of gender differences in verapamil pharmacokinetics is also possible.     

Pharmacokinetics of verapamil in patients with hypertension

Summary Twelve hypertensive patients (WHO Stage I-II) were given oral verapamil (Isoptin) b.d. or t.d.s. as long-term treatment. The pharmacokinetics of verapamil and norverapamil were studied both after single and b.d. and t.d.s. doses of verapamil 240, 360 or 480 mg daily adjusted according to the blood pressure response. The apparent oral clearance of verapamil was decreased after both the twice and thrice daily dosage regimens (1.38 and 1.841/min, respectively) as compared to the single dose (4.39 l/min). The plasma half-life of verapamil was increased from 3.34 h (single dose) to 4.65 h (b.i.d.). Decreased elimination of norverapamil was also found after multiple doses of verapamil, as shown by an increase in the adjusted AUC of norverapamil (adjusted to a verapamil dose of 80 mg), namely from 574.9 h·ng·ml^–1 (single dose) to 1172 h·ng·ml^–1 (b.d.) and to 841 h·ng·ml^–1 (t.d.s.). The plasma half-life of norverapamil increase from 5.68 h to 7.34 h during twice daily dosing. During thrice daily verapamil, no increase in plasma half-life was found either for verapamil or norverapamil, probably due to the relatively short sampling time (6 h). The plasma concentration of verapamil and the reduction in supine systolic and diastolic blood pressure were correlated. The mean decrease in supine systolic blood pressure was 5.8 mm Hg per 100 ng verapamil/ml plasma, and for diastolic pressure 2.9 mm Hg per 100 ng verapamil/ml plasma. The mean steadystate plasma concentrations of verapamil were similar after twice and thrice daily dosing regimens, which agrees with the clinical observation that blood pressure control in hypertensive patients is as good after verapamil b.d. and t.d.s.     

Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

Aim:

Losartan and antiplatelet agent ticlopidine can be prescribed concomitantly for prevention or therapy of cardiovascular diseases. Hence, the effects of ticlopidine on the pharmacokinetics of losartan and its active metabolite EXP-3174 were evaluated in rats.

Methods:

Ticlopidine (4 or 10 mg/kg po) was administered 30 min before administration of losartan (9 mg/kg po or 3 mg/kg iv). The activity of human CYP2C9 and 3A4 were measured using the CYP inhibition assay kit. The activity of P-gp was evaluated using rhodamine-123 retention assay in MCF-7/ADR cells.

Results:

Ticlopidine (10 mg/kg) significantly increased the areas under the plasma concentration-time curves (AUCs) and peak plasma concentration (C_max) of oral losartan (9 mg/kg), as well as the AUCs of the active metabolite EXP-3174. Ticlopidine (10 mg/kg) did not significantly change the pharmacokinetics of intravenous losartan (3 mg/kg). Ticlopidine inhibited CYP2C9 and 3A4 with IC₅₀ values of 26.0 and 32.3 μmol/L, respectively. The relative cellular uptake of rhodamine-123 was unchanged.

Conclusion:

The significant increase in the AUC of losartan (9 mg/kg) by ticlopidine (10 mg/kg) could be attributed to the inhibition of CYP2C9- and 3A4-mediated losartan metabolism in small intestine and/or in liver. The inhibition of P-gp in small intestine and reduction of renal elimination of losartan by ticlopidine are unlikely to be causal factors.     

Pharmacokinetics of clarithromycin in rats with acute renal failure induced by uranyl nitrate

In rats pretreated with dexamethasone (an inducer of CYP3A1/2 in rats) and troleandomycin (an inhibitor of CYP3A1/2 in rats), the area under the plasma concentration-time curve from time zero to time infinity (AUC) values of clarithromycin were significantly smaller (365 compared with 600 micro g min/ml) and greater (1410 compared with 581 micro g min/ml), respectively, than those in control rats. This indicated that clarithromycin was metabolized via CYP3A1/2 in rats. The expression of CYP3A1(23) increased in rats with acute renal failure induced by uranyl nitrate (rats with U-ARF). Hence, it could be expected that AUC of clarithromycin could be smaller in rats with U-ARF. However, after intravenous administration of clarithromycin at a dose of 20mg/kg, the AUC and time-averaged total body (Cl) and nonrenal (Cl(nr)) clearance values were comparable between the two groups of rats. The 9000 x g supernatant fraction of liver homogenates in rats with U-ARF had comparable metabolic activities for clarithromycin compared with those in control rats, suggesting that the CYP3A isozyme responsible for metabolism of clarithromycin seemed not to be expressed considerably in the rats. This could explain the comparable AUC, Cl and Cl(nr) values of clarithromycin between the two groups of rats.     

Effects of water deprivation on the pharmacokinetics of metformin in rats

It was reported that metformin was mainly metabolized via hepatic CYP2C11, 2D1 and 3A1/2 in rats, and in a rat model of dehydration, the expressions of hepatic CYP2C11 and 3A1/2 were not changed. Hence, it could be expected that the Cl(nr) of metformin is comparable between two groups of rats if the contribution of CYP2D1 in the rat model of dehydration is not considerable. It was also reported that the timed-interval renal clearance of metformin was dependent on the urine flow rate in rats. In the rat model of dehydration, the 24 h urine output was significantly smaller than in the controls. Hence, the urinary excretion of metformin was expected to be smaller than the controls. The above expectations were proven as follows. After intravenous administration of metformin (100 mg/kg) to the rat model of dehydration, the Cl(nr) were comparable between the two groups of rats. After both intravenous and oral administration of metformin (both 100 mg/kg) to the rat model of dehydration, the 24 h urinary excretion of the drug was significantly smaller than in the controls. After oral administration of metformin to the rat model of dehydration, the AUC was significantly greater (99.2% increase) than the controls.     

Pharmacokinetics of omeprazole in rats with water deprivation for 72 hours

Dehydration can occur by excessive sweating, polyuria, severe diarrhea and hyperthermia. Previous studies reported that the expressions of CYP1A1/2 and 3A1(23)/2 were not changed in male Sprague-Dawley rats with 72 h water deprivation (dehydrated rats), and that the metabolism of omeprazole is mainly catalysed via CYP1A1/2, 2D1 and 3A23/2 in rats. Hence, it could be expected that the hepatic metabolism of omeprazole would not be changed considerably in dehydrated rats, if the contribution of CYP2D1 to the metabolism of omeprazole in dehydrated rats is not considerable. Therefore, the pharmacokinetics of omeprazole were compared after intravenous (20 mg/kg) and oral (40 mg/kg) administration in control rats and in dehydrated rats. After intravenous administration, the time-averaged nonrenal clearance (Cl(nr)) values of omeprazole were comparable between the two groups of rats. This could be supported by comparable in vitro intrinsic clearance (Cl(int)) values for the disappearance of omeprazole in rat hepatic microsomes and the comparable free (unbound to plasma proteins) fractions of omeprazole in plasma in the two groups of rats. After oral administration, the AUC values of omeprazole were also comparable in the two groups of rats. The above data suggest that the dehydration state did not affect considerably the pharmacokinetics of omeprazole in rats.     

Gender specific association of CYP2C9*3 with hyperlipidaemia in Chinese

AIMS: To investigate the association of CYP2C9*3 and *6 with hyperlipidaemia in Chinese. METHODS: Four hundred and seventy-six Chinese participated in the study, including 211 uncomplicated hyperlipidaemic patients and 265 healthy controls. PCR-RFLP was used to identify CYP2C9*3 and *6. RESULTS: CYP2C9*6 was not detected in this study. The allelic frequency of CYP2C9*3 was 0.039 (95% CI 0.022, 0.056). A nonsignificant difference existed in CYP2C9*3 frequencies between males and females (P = 0.605, OR = 1.194, 95% CI 0.610, 2.336), patients and controls (P = 0.063, OR = 0.506, 95% CI 0.244, 1.049) in the total population. However, in the female group, CYP2C9*3 frequency in patients with hyperlipidaemia was significantly lower than that in controls (P < 0.0001, OR = 0.062, 95% CI 0.008, 0.476). CONCLUSIONS: The association of CYP2C9*3 with hyperlipidaemia was specific for females in this Chinese population.     

Effects of oral epigallocatechin gallate on the oral pharmacokinetics of verapamil in rats

Verapamil is known to be a P‐glycoprotein (P‐gp) substrate and norverapamil is formed via hepatic cytochrome P450 (CYP 3A) in the rat. Epigallocatechin gallate (EGCG), a flavonoid, was reported to be an inhibitor of both P‐gp and CYP3A. Hence, it could be expected that EGCG could alter the pharmacokinetics of verapamil. In this study, 9 mg/kg verapamil was administered orally to Sprague–Dawley rats 30 min after the oral administration of 2 and 10 mg/kg of oral EGCG. Compared with the controls, the AUC values of both verapamil (74.3% and 111% increase for 2 and 10 mg/kg EGCG, respectively) and norverapamil (51.5% and 87.2% increase for 2 and 10 mg/kg EGCG, respectively) were significantly greater in the presence of EGCG. However, compared with the controls, both the AUC and the relative bioavailability of verapamil were significantly (p<0.01) increased by 74.3–111% in the presence of EGCG. The likely explanation is inhibition of P‐gp. Inhibition of CYP3A would increase the AUC of verapamil but decrease the AUC of norverampil. However, inhibition of P‐gp would lead to an increase of AUC of both verapamil and norverapamil. Copyright © 2009 John Wiley & Sons, Ltd.