Pharmacokinetics of verapamil in patients with renal failure

Summary The pharmacokinetics of verapamil was studied in patients with end-stage chronic renal failure and in normal subjects after i.v. injection of 3 mg and a single oral dose of 80 mg. Plasma levels of verapamil and its active metabolite norverapamil were measured by HPLC. After i.v. injection, the terminal phase half-life and total plasma clearance of verapamil in both groups were similar. Haemodialysis did not change the time course of plasma verapamil levels after i.v. administration. After a single oral dose, the plasma levels of verapamil and norverapamil in both groups of subjects were similar. Subsequently, normal volunteers and patients with renal failure were treated for 5 days with oral verapamil 80 mg t.d.s. There was no difference between the 2 groups of subjects in the trough and peak levels of verapamil or of norverapamil. Intravenous and oral administration of the calcium channel blocking agent had similar effects on blood pressure, heart rate and the PR-interval in the electrocardiogram in both groups. The study demonstrated that the disposition of verapamil was similar in normal subjects and in patients with renal failure.Some of the results were presented at the Joint Spring Meeting of the German Pharmacological and Physiological Societies in Mainz, 1983 (Schols et al. 1983)     

An evaluation of the pharmacokinetics, pharmacodynamics, and dialyzability of verapamil in chronic hemodialysis patients

The pharmacokinetics and pharmacodynamics of verapamil were investigated in six chronic hemodialysis patients. A single oral 120-mg dose was administered both on a non-hemodialysis day and a hemodialysis day separated by greater than or equal to 7 days. Blood pressure and PR interval were measured simultaneously with each blood sample. Plasma verapamil and norverapamil concentrations were analyzed by high pressure liquid chromatography. The mean Cmax, tmax, AUC, apparent plasma clearance, and terminal t 1/2 were 190 +/- 108 ng/mL, 0.6 +/- 0.2 hour, 676 +/- 443 ng.hr/mL, 3926 +/- 1933 mL/min, and 11.4 +/- 4.0 hr, respectively, on the nonhemodialysis day. The dialysis clearance of verapamil and norverapamil was negligible. The t 1/2 during hemodialysis was 3.6 +/- 1.1 hr, compared with 3.4 +/- 0.7 hr during the same period of time postdose on the nonhemodialysis day (NS, P greater than .05). Systolic and diastolic blood pressure decreased for up to 4 hours postdose, whereas the PR interval tended to increase. Conclusions include: (1) the single oral-dose pharmacokinetics and pharmacodynamics of verapamil in chronic hemodialysis patients are similar to published data in normal subjects and cardiac patients and (2) verapamil and norverapamil are not significantly removed by hemodialysis, so that supplemental doses are not necessary.     

Systemic availability of oral verapamil and effect on PR interval in man.

1 The plasma levels of verapamil and its major metabolite norverapamil were related to its effect as a Ca-antagonist on atrio-ventricular (AV) conduction, judged from prolongation of the PR interval in six normal volunteers. 2 Intravenous administration (0.1 mg kg-1) was compared to oral administration (120 mg) in each subject. 3 Intravenous verapamil showed a mean distribution half-life (alpha) of 8.5 min and elimination half-life (beta) of 2.0 h. The volume of distribution was about 112.1. Oral dosage gave an elimination half-life of 2.7 h, and a norverapamil half-life which averaged 4.6 h. The bioavailability of the oral dose averaged 22% (17 to 29%). 4 After the oral dose the percentage change in PR interval in the five appropriate subjects correlated significantly with the log plasma verapamil level (r = 0.732), but not with the log plasma norverapamil level (r = 0.078); norverapamil could not be detected after the intravenous dose. One subject developed Wenckebach type second degree AV block after each dose.     

Pharmacokinetics of nitrendipine in terminal renal failure

Summary The pharmacokinetics and plasma protein binding of nitrendipine in patients with terminal renal failure have been compared with those in subjects with normal renal function.Kinetic parameters were calculated after a single 40 mg oral dose, an i.v. injection of 3 mg and after a 15 mg i.v. infusion of nitrendipine. Steady-state plasma levels were determined after 5 days of oral treatment with 20 mg b.d.Pharmacokinetic parameters and steady-state plasma levels in patients with renal failure did not differ from those in subjects with normal renal function.Nitrendipine was as highly bound to plasma proteins in patients with renal failure, as in subjects with normal renal function. The plasma protein did not differ between the two.The dosage of nitrendipine need not be modified for kinetic reasons in patients with renal failure.     

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 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.     

Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure

Summary The total and free steady-state plasma levels of nifedipine in patients with renal failure have been compared with those in subjects with normal renal function. Studies were done after administration of nifedipine 10 mg t.d.s. p.o. for 5 days, after i.v. infusion of 4·4 mg, and after a single 10 mg oral dose.The systemic clearance of nifedipine after a single i.v.-dose was higher in subjects with renal insufficiency (854 ml/min) than in those with normal renal function (468 ml/min). After the single oral dose the AUC (6100 ng·min·ml^–1) and maximum plasma concentration (75.0 ng·ml^–1) were lower than in subjects with normal renal function (19300 ng·ml^–1; 122 ng·ml^–1). The plasma protein binding of nifedipine averaged 95.5% in normal subjects and 94.8% in patients with renal failure.Although free and total steady-state plasma levels of nifedipine tended to be somewhat lower than normal in renal failure, the changes in pharmacokinetics and decreased protein binding of nifedipine did not result in a significantly different steady-state plasma level of the drug. The blood pressure response to a given plasma nifedipine level appeared to be enhanced in renal failure.     

Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite,norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin

This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5–64.8%, and the peak plasma concentration (C_max) of verapamil by 34.1–65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (T_max) and the terminal half-life (t_1/2) of verapamil in the presence of lovastatin. The AUC and C_max of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.     

Plasma levels and urinary excretion of verapamil, norverapamil, N-dealkylverapamil (D617), N-dealkylnorverapamil (D620) following oral administration of a slow-release preparation

The kinetics of verapamil and of its N-dealkylated metabolites (norverapamil, D617, D620) were studied in six cardiac patients with normal cardiac indexes after 120 mg oral administration of the drug both as conventional preparation and as slow-release preparation. Following a dose of the slow-release preparation, the drug concentration curves were smoother and the mean bioavailability was lower in comparison with the conventional preparation. A patient taking inducing agents (phenobarbital and phenytoin) exhibited a strikingly low bioavailability. Following administration of the conventional preparation, the mean plasma half-lives of verapamil, norverapamil, D617 and D620 were 4.4, 6.6, 8.5, and 15.8 h respectively and the drug concentrations showed a triexponential decay. Urinary excretion data indicate that a saturation phenomenon may occur at level of renal tubular transport and that a competition may be suspected between D620 and the other compounds. It is concluded that various mechanisms, i.e. changes in hepatic and renal clearances, occurrence of a deep compartment, and the properties of the pharmaceutical preparation may affect verapamil kinetics during long-term treatment.     

Enhanced bioavailability of verapamil after oral administration with hesperidin in rats

The aim of this study was to investigate the effects of hesperidin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of hesperidin (3 or 10 mg/kg). Compared to the control group, the presence of hesperidin significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 71.1–96.8% and the peak concentration (C_max) of verapamil by 98.3–105.2%. Hesperidin significantly (p<0.01) decreased the total plasma clearance (CL/F) of verapamil by 41.6–49.2% in rats. However there was no significant change in the time to reach the peak plasma concentration (T_max), the elimination rate constant (K_el) and the terminal half-life (T_1/2) of verapamil in the presence of hesperidin. The AUC and C_max of norverapamil were significantly (p<0.05) higher in rats coadministrated with hesperidin than those of the control. Consequently hesperidin significantly enhanced bioavailability of verapamil in rats. These results might be due to the decreased efflux and metabolism of verapamil in the intestine. Drug interactions should be concerned in the clinical setting when verapamil is used concomitantly with hesperidin or hesperidin-containing dietary.     

Pharmacokinetics of verapamil and its major metabolite, nor-verapamil from oral administration of verapamil in rabbits with hepatic failure induced by carbon tetrachloride

The aim of this study was to investigate the pharmacokinetic changes of verapamil and its major metabolite, norverapamil, after oral administration of verapamil (10 mg/kg) in rabbits with slight, moderate and severe hepatic failure induced by carbon tetrachloride. The plasma verapamil concentrations in all groups of hepatic failure were significantly higher (p < 0.01) than the control. However, the plasma norverapamil concentrations in severe hepatic failure were significantly higher (p < 0.05) than the control. The peak concentrations (Cmax) and the areas under the plasma concentration-time curve (AUC) of verapamil in the rabbits were significantly (p<0.01) higher than the control. The absolute bioavailability (F(A.B)) and the relative bioavailability (F(R.B)) of verapamil in the rabbits with hepatic failure were significantly higher (13.6-22.2% and 150-244%, respectively) than the control (9.1% and 100%, respectively). Although the AUC and Cmax of its major metabolite, norverapamil, in slight, moderate hepatic failure were not significantly lower than the control, the metabolite-parent AUC ratio in all groups of hepatic failure was decreased significantly (p < 0.05, in slight group; p < 0.01, in moderate and severe group) than the control. This could be due to decrease in metabolism of verapamil in the liver because of suppressed hepatic function in the hepatic failure groups because verapamil is mainly metabolized in the liver. From our data, it would seem appropriate that in patients with liver disease, doses of verapamil should be decreased by degree of hepatic failure.     

Dietary salt does not influence the disposition of verapamil enantiomers in relation to efflux transporter ABCB1 genetic polymorphism in healthy Korean subjects

To evaluate the effects of dietary salt on the stereoselective disposition of verapamil enantiomers in relation to the transporter ABCB1 2677GG/3435CC and 2677TT/3435TT haplotypes, ten healthy subjects were asked to take diets of three different salt levels for 7 days in a randomized, three-way crossover manner. The plasma concentrations of verapamil and norverapamil enantiomers were determined after a single oral dose of 240 mg verapamil on the last day of each phase. Pharmacokinetic parameters were calculated by non-compartmental analysis techniques and compared among the three different dietary salt phases. Compared with the medium salt diet, the high and low salt diets had no significant effect on the disposition of verapamil enantiomers. Moreover, the ABCB1 haplotypes did not alter the impact of dietary salt, although ABCB1 2677TT/3435TT subjects had slightly, but not significantly, higher C(max) and area under the curve (AUC) and lower T(max) for the verapamil enantiomers than did 2677GG/3435CC subjects in each salt phase.     

Pharmacokinetics of loratadine in patients with renal insufficiency

The disposition of loratadine, a new orally active histamine H1 receptor antagonist and its primary metabolite descarboethoxyloratadine were characterized in adult volunteers with normal renal function (group I), patients with chronic renal failure, i.e., creatinine clearance less than 30 mL/min (group II), as well as chronic hemodialysis patients (group III). The effect of hemodialysis on the disposition of loratadine and descarboethoxyloratadine was also assessed. Subjects in groups I and II were given a single oral 40 mg dose of loratadine while the patients in Group III received two single 40 mg doses of loratadine (during an interdialytic period and just prior to hemodialysis). Loratadine was rapidly absorbed and the decline of plasma concentrations after attainment of the Cmax was biexponential in all subjects. No significant differences in t1/2 beta were observed between the three groups (8.7 +/- 5.9, 7.6 +/- 6.9, 8.6 +/- 1.6 hrs: in groups I, II, and III, respectively). The apparent total body clearance and apparent volume of distribution of loratadine also did not differ significantly among the three groups. No significant differences in the Cmax or tmax of the metabolite were observed. The metabolite AUC infinity 0 however was significantly greater in group II subjects: (212.4 +/- 37.8, 469.5 +/- 95.4, 325.2 +/- 114.6 ng.hr/mL; groups I, II, and III, respectively). No significant relationship was observed between the terminal elimination half-life of loratadine or descarboethoxyloratadine and creatinine clearance. Hemodialysis augmented endogenous clearance by less than 1%. The disposition of loratadine is not significantly altered in patients with severe renal insufficiency nor is hemodialysis an effective means of removing loratadine or descarboethoxyloratadine from the body.     

Pharmacokinetics of ranitidine in patients with renal failure

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6-54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378-808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half-life following oral administration was 8.5 +/- 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% +/- 10.5%. After IV administration, the elimination half-life, plasma clearance, renal clearance, and volume of distribution were 7.0 +/- 1.0 hours, 170 +/- 38 mL/min, 36.0 +/- 25.0 mL/min, and 1.3 +/- 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P less than .05) after IV administration. The elimination half-life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2-blocking activity.     

Bioavailability of labetalol in patients with end-stage renal disease.

The pharmacokinetics and pharmacodynamics of labetalol were assessed after a single oral and intravenous dose in eight patients with end-stage renal disease (ESRD) maintained on chronic hemodialysis, and in eight age-and sex-matched normal volunteers. The mean area under the serum concentration-time curve, volume of distribution, clearance, and terminal elimination half-life values after a single intravenous dose of 0.5 mg/kg of labetalol were not significantly different between ESRD patients and normal volunteers. Similarly, the absolute bioavailability of an oral dose of 200 mg of labetalol was 0.33 in ESRD patients and was not significantly different from that of normal volunteers (0.26). However, a significant decrease in the area under the mean blood pressure-time curve was found after a single oral dose in ESRD patients, which was not observed in normal volunteers. The pharmacokinetics of labetalol were not associated with changes in blood pressure. Thus, when given orally to the ESRD patient, labetalol should be slowly titrated and the blood pressure closely monitored.     

The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits

We have investigated the effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. Pharmacokinetic parameters of verapamil and norverapamil were determined after the oral administration of verapamil (10 mg kg(-1)) to rabbits in the presence and absence of quercetin (5.0 and 15 mg kg(-1)). While co-administration of quercetin concurrently was not effective to enhance the oral exposure of verapamil, pretreatment of quercetin 30 min before verapamil administration significantly altered the pharmacokinetics of verapamil. Compared with the control group (given verapamil alone), the C(max) and AUC of verapamil increased approximately twofold in the rabbits pretreated with 15 mg kg(-1) quercetin. There was no significant change in T(max) and terminal plasma half-life (t(1/2)) of verapamil in the presence of quercetin. Consequently, absolute and relative bioavailability values of verapamil in the rabbits pretreated with quercetin were significantly higher (P < 0.05) than those from the control group. Metabolite-parent AUC ratio in the rabbits pretreated with quercetin decreased by twofold compared with the control group, implying that pretreatment of quercetin could be effective to inhibit the CYP3A4-mediated metabolism of verapamil. In conclusion, pretreatment of quercetin significantly enhanced the oral exposure of verapamil. This suggested that concomitant use of quercetin or a quercetin-containing dietary supplement with verapamil requires close monitoring for potential drug interaction.     

Therapeutic aminoglycoside monitoring in renal failure patients

In patients with normal renal function, defined peak (5-10 mg/L) and trough levels (less than 2 mg/L) for gentamicin, tobramicin, and netilmicin are considered therapeutic. Netilmicin peak and trough levels were investigated in 50 patients requiring hemodialysis due to acute (70%) or permanent (30%) renal failure. Netilmicin was given at a dosage interval of 24 h, with a loading dose on the first day (1.5 mg/kg) and a reduced daily maintenance dose (0.5 mg/kg) supplemented to the posthemodialysis dosage (1.3 mg/kg) after each hemodialysis. As compared with studies on patients not requiring hemodialysis, mortality (44%) was higher, mainly due to uncontrolled infection, whereas ototoxicity (17%) was not. Peak (5.9 +/- 1.7 mg/L) and trough plasma levels (3.0 +/- 0.9 mg/L) were significantly lower in patients who did not respond and died than were peak (8.2 +/- 2.5 mg/L) and trough (3.8 +/- 1.2 mg/L) levels in patients responding to aminoglycoside treatment. In renal failure patients, there is obviously not only the risk of overdosing and toxic side effects but also the risk of insufficient bactericidal effect as a result of underdosing. Consequently, by use of an aminoglycoside dosage similar to the present schedule, peak levels (5-10 mg/L) as desired in normal subjects but trough levels (2.5-5 mg/L) that are considerably higher than in normal subjects should be the target concentrations for patients with advanced renal failure.     

Rabeprazole: pharmacokinetics and tolerability in patients with stable, end-stage renal failure.

The authors compare the pharmacokinetic profiles, safety, and tolerability of rabeprazole, a new proton pump inhibitor (PPI), in healthy volunteers and in subjects with stable, end-stage renal failure. This single-center, open-label trial included two groups of subjects: 10 healthy males with 24-hour creatinine clearance > or = 90 mL/min/m2 and 10 males with renal failure (24-hour creatinine clearance < or = 5 mL/min/m2) receiving hemodialytic therapy. Normal subjects received a single, oral 20 mg rabeprazole dose. Those with renal failure received a 20 mg dose of rabeprazole on the day after hemodialysis and a second dose after a 2-week washout period during dialysis. Blood samples were drawn before and up to 24 hours after rabeprazole administration for determination of plasma rabeprazole concentrations by high-performance liquid chromatography. Safety and tolerability of rabeprazole were determined by reporting adverse events and comparing vital signs, ECG, physical examinations, and clinical laboratory tests before and during treatment. Comparison of pharmacokinetic results from healthy volunteers with those from subjects with renal failure indicated no clinically significant differences between groups. In addition, there were no statistically significant differences between any pharmacokinetic parameters recorded during or after hemodialysis. Rabeprazole was well tolerated by both groups. Only two drug-related adverse events were reported, and there were no significant treatment-emergent changes in vital signs or ECG. Treatment-emergent changes in hematologic and clinical chemistry parameters were observed for a few subjects in each group and generally represented only slight deviations from the normal range. These results indicate that no dosage adjustment of rabeprazole is required in patients with renal dysfunction. These findings and the well-documented clinical efficacy of this new PPI in patients with gastric ulcers, duodenal ulcers, or gastroesophageal reflux disease support rabeprazole's use in the treatment of patients with acid peptic disorders.     

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.     

Verapamil and norverapamil in plasma and breast milk during breast feeding

Summary The concentrations of verapamil and norverapamil have been measured in milk and plasma samples from a 32year-old woman treated with verapamil 80 mg tds while breast-feeding her child.The average steady-state concentrations of verapamil and norverapamil in milk were, respectively, 60% and 16% of the concentrations in plasma.The breast-fed child received less than 0.01% of the dose of verapamil given to the mother. No verapamil or norverapamil (<1 ng/ml) could be detected in the plasma from the child.