Oral Administration Of Diltiazem Research Articles

Repeated dosing of piperine induced gene expression of P‐glycoprotein via stimulated pregnane‐X‐receptor activity and altered pharmacokinetics of diltiazem in rats

This study investigated the effect of piperine on the gene expression of P-glycoprotein (P-gp) as well as pregnane-X-receptor (PXR) activity and also its implication on the bioavailability of diltiazem, a P-gp substrate. The effect of piperine on the systemic exposure of diltiazem was examined in rats after the intravenous and oral administration of diltiazem with/without 2 week pretreatment with piperine. Compared with the control group given diltiazem (20 mg/kg) alone, the pretreatment with piperine (10 or 20 mg/kg, once daily for 2 weeks) decreased the oral exposure of diltiazem by 36-48% in rats. Consequently, the bioavailability of oral diltiazem was significantly lower (p < 0.05) after the 2 week pretreatment with piperine. The pretreatment with piperine for 2 weeks also reduced the systemic exposure of desacetyldiltiazem, a major active metabolite of diltiazem by approximately 73%, accompanied by a significant decrease in the metabolite-parent ratio. In contrast to the oral pharmacokinetics, piperine did not affect the intravenous pharmacokinetics of diltiazem in rats. Immunoblot analysis indicated that the protein expression level of intestinal P-gp was significantly enhanced after the 2 week pretreatment with piperine in rats. In addition, piperine increased the PXR reporter activity in human hepatoma cells. Taken together, the 2 week pretreatment with piperine significantly induced intestinal P-gp expression in conjunction with stimulated PXR activity and decreased the oral exposure of diltiazem and desacetyldiltiazem in rats.

Effects of Ticlopidine on the Pharmacokinetics of Diltiazem and Its Main Metabolite, Desacetyldiltiazem, in Rats

The purpose of this study was to investigate the effect of ticlopidine on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 <TEX>$mg{\cdot}kg^{-1}$</TEX>) with ticlopidine (3 or 9 <TEX>$mg{\cdot}kg^{-1}$</TEX>). The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activities were also evaluated. Ticlopidine inhibited CYP3A4 enzyme activity in a concentrationdependent manner with a 50% inhibition concentration (<TEX>$IC_{50}$</TEX>) of 35 <TEX>${\mu}M$</TEX>. In addition, ticlopidine did not significantly enhance the cellular accumulation of rhodamine-123 in NCI/ADR-RES cells overexpressing P-gp. Compared with the control (given diltiazem alone), ticlopidine significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration (<TEX>$C_{max}$</TEX>) and the area under the plasma concentration-time curve (AUC) of diltiazem were significantly (9 <TEX>$mg{\cdot}kg^{-1}$</TEX>, p<0.05) increased in the presence of ticlopidine. The AUC of diltiazem was increased by 1.44-fold in rats in the presence of ticlopidine (9 <TEX>$mg{\cdot}kg^{-1}$</TEX>). Consequently, the absolute bioavailability (A.B.) of diltiazem in the presence of ticlopidine (9.3-11.5%) was signifi cantly higher (9 <TEX>$mg{\cdot}kg^{-1}$</TEX>, p<0.05) than that in the control group (8.0%). Although ticlopidine significantly (p<0.05) increased the AUC of desacetyldiltiazem, the metabolite-parent AUC ratio (M.R.) in the presence of ticlopidine (9 <TEX>$mg{\cdot}kg^{-1}$</TEX>) was significantly decreased compared to that in the control group, implying that ticlopidine could effectively inhibit the metabolism of diltiazem. In conclusion, the concomitant use of ticlopidine significantly enhanced the oral bioavailability of diltiazem in rats by inhibiting CYP3A4-mediated metabolism in the intestine and/or liver rather than by inhibiting intestinal P-gp activity or renal elimination of diltiazem.

Glycoregulation is not Altered by Short-Term Administration of Diltiazem in Nondiabetic Humans

In this study changes in glucose assimilation during an intravenous glucose tolerance test (IVGTT) was investigated in 12 clinically healthy normotensive women with a body mass index (BMI) of 25 kg/m2 (range 22-31). This was assessed by coefficient Kg, the level of glycosylated proteins and insulin, C-peptide and contraregulating hormone secretion after seven days of oral administration of diltiazem, a calcium current blocker (180 mg per day). In spite of the fact that diltiazem protracted electrocardiographic QT interval from 0.16 +/- 0.008 to 0.18 +/- 0.009 s. (p < 0.01), QaT from 0.29 +/- 0.007 to 0.31 +/- 0.008 s. (p < 0.05), QeT from 0.35 +/- 0.009 to 0.37 +/- 0.009 s. (p < 0.01), it did not affect Kg in any significant way, nor did it affect the glycosylated protein levels, insulin and C-peptide secretion, nor the secretion of adrenaline, noradrenaline, dopamine, cortisol and growth hormone. Thus although diltiazem is a highly effective drug as far as the cardiovascular system is concerned, short-term administration of therapeutic doses of 180 mg/day is not associated with glycoregulatory risks.

Influence of diltiazem in combination with a sucrose-rich diet on gingival alterations in rats

The aim of this study was to evaluate the influence of diltiazem in combination with a sucrose-rich diet on gingival alterations in rats. One hundred and twenty male Holtzman rats were randomly assigned to 10 groups (n = 12), being 2 control groups treated with saline and 8 test groups treated with diltiazem in daily doses of 5, 25, 50 and 100 mg/kg during 40 or 60 days. Afterwards, the mandibles were removed for macroscopic, histologic and histometric analyses of the buccal gingiva of the mandibular right first molar. No macroscopic characteristic of gingival overgrowth was observed in any of the groups. The microscopic analysis showed characteristics of normality with inflammatory cells only adjacent to the crevicular epithelium in all groups for both periods. The histometric analysis showed significant differences only for the epithelial tissue area in the 40-day period (Kruskal-Wallis; P = 0.032). Comparing the periods, significant differences regarding the connective and epithelial tissue areas were observed only in the group treated with a 25 mg/kg dose (Mann-Whitney; P = 0.004 and P = 0.007, respectively). Oral administration of diltiazem in combination with a sucrose-rich diet did not induce gingival alterations in rats.

Effects of Resveratrol on the Pharmacokinetics of Diltiazem and Its Major Metabolite, Desacetyldiltiazem, in Rats

The purpose of this study was to investigate the effects of resveratrol, an antioxidant, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. The pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after an oral administration of diltiazem (15 mg/kg) to rats in the presence and absence of resveratrol (0.5, 2.5, and 10 mg/kg). Compared to the control group, the presence of resveratrol significantly (P < 0.05) increased the area under the plasma concentration-time curve (AUC) of diltiazem, except for resveratrol 0.5 mg/kg. Consequently, the absolute bioavailability (AB) of diltiazem in the presence of resveratrol (2.5 and 10 mg/kg) was significantly (P < 0.05) higher (10.2-11.1%) than that of the control (6.9%). The relative bioavailability (RB) of diltiazem in the presence of resveratrol (2.5 and 10 mg/kg) was increased by 1.48- to 1.60-fold. Resveratrol did not alter absorption rate constant (K(a)) and the time to reach the peak concentration (T(max)) of diltiazem. The AUC of desacetyldiltiazem was increased significantly (P < 0.05) in the presence of 10 mg/kg of resveratrol. The metabolite-parent AUC ratio (MR) in the presence of resveratrol was decreased but did not show significant change. In conclusion, resveratrol significantly increased the bioavailability of diltiazem due to the inhibition of both the cytochrome P450 (CYP) 3A4-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or liver. Based on these results, if these results would be confirmed in clinical experiments, the dosage of diltiazem should be readjusted when diltiazem is used concomitantly with resveratrol.

Effect of atorvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats

The purpose of this study was to investigate the effect of atorvastatin, HMG-CoA reductase inhibitor, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 mg x kg(-1)) to rats pretreated with atorvastatin (0.5 or 2.0 mg x kg(-1)). Compared with the control (given diltiazem alone), the pretreatment of atorvastatin significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration (Cmax) and the areas under the plasma concentration-time curve (AUC) of diltiazem were significantly (p < 0.05, 0.5 mg x kg(-1); p < 0.01, 2.0 mg x kg(-1)) increased in the presence of atorvastatin. The AUC of diltiazem was increased by 1.40-fold in rats pretreated with 0.5 mg x kg(-1) atorvastatin, and 1.77-fold in rats pretreated with 2.0 mg x kg(-1) atorvastatin. Consequently, absolute bioavailability values of diltiazem pretreated with atorvastatin (8.4-10.6%)were significantly higher (p < 0.05) than that in the control group (6.6%). Although the pretreatment of atorvastatin significantly (p < 0.05) increased the AUC of desacetyldiltiazem, metabolite-parent AUC ratio (M.R.) in the presence of atorvastatin (0.5 or 2.0 mg x kg(-1)) was significantly decreased compared to the control group, implying that atorvastatin could be effective to inhibit the metabolism of diltiazem. In conclusion, the concomitant use of atorvastatin significantly enhanced the oral exposure of diltiazem in rats.

Effects of morin pretreatment on the pharmacokinetics of diltiazem and its major metabolite, desacetyldiltiazem in rats

The purpose of this study was to investigate the effect of morin, a flavonoid, on the pharmaco-kinetics of diltiazem and one of its metabolites, desacetyldiltiazem in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after oral administration of diltiazem (15 mg/kg) in rats pretreated with morin (1.5, 7.5, and 15 mg/kg). Compared with the control group (given diltiazem alone), pretreatment of morin significantly increased the absorption rate constant (Ka) and peak concentration (Cmax) of diltiazem (p<0.05, p<0.01). Area under the plasma concentration-time curve (AUC) of diltiazem in rats pretreated with morin were significantly higher than that in the control group (p<0.05., p<0.01), hence the absolute bioavailability (AB%) of diltiazem was significantly higher than that of the control group (p<0.05, p<0.01). Relative bioavailability (RB%) of diltiazem in rats pretreated with morin was increased by 1.36-to 2.03-fold. The terminal half-life (t1/2) and time to reach the peak concentration (Tmax) of diltiazem were not altered significantly with morin pretreatment. AUC of desacetyldiltiazem was increased significantly (p<0.05) in rats pretreated with morin at doses of 7.5 and 15 mg/kg, but metabolite-parent ratio (MR) of desacetyldiltiazem was decreased significantly (p<0.05), implying that pretreatment of morin could be effective to inhibit the CYP 3A4-mediated metabolism of diltiazem. There were no apparent changes of Tmax and t1/2 of desacetyldiltiazem with morin pretreatment. Collectively, the pretreatment of morin significantly altered pharmacokinetics of diltiazem, which can be attributed to increased intestinal absorption as well as reduced first-pass metabolism. Based on these results, dose modification should be taken into consideration when diltiazem is used concomitantly with morin or morin-containing dietary supplements in clinical setting.

Pharmacokinetic interaction between fluvastatin and diltiazem in rats

The present study aimed to investigate the effect of fluvastatin on the pharmacokinetics of diltiazem in rats. Pharmacokinetic parameters of diltiazem were determined in rats following an oral administration of diltiazem (15 mg/kg) in the presence and absence of fluvastatin (0.6 and 2.0 mg/kg). Compared with the control given diltiazem alone, the C(max) and AUC of diltiazem increased by 30-70% in rats with the concurrent use of fluvastatin, while there was no significant change in T(max) and the plasma half-life (T(1/2)) of diltiazem. Consequently, absolute and relative bioavailability values of diltiazem in the presence of fluvastatin were significantly higher (p<0.05) than those from the control group, implying that fluvastatin could reduce the presystemic extraction of diltiazem. In conclusion, the concurrent use of fluvastatin significantly enhanced the oral exposure of diltiazem in rats.

Enhanced oral exposure of diltiazem by the concomitant use of naringin in rats

The present study aims to investigate the effect of naringin, a flavonoid, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats following an oral administration of diltiazem (15 mg kg −1) to rats in the presence and absence of naringin (5 and 15 mg kg −1). Compared to the control given diltiazem alone, the C max and AUC of diltiazem increased by twofolds in rats pretreated with naringin, while there was no significant change in T max and terminal plasma half-life ( T 1/2) of diltiazem. Consequently, absolute and relative bioavailability values of diltiazem in the presence of naringin were significantly higher ( p < 0.05) than those from the control group. Metabolite–parent AUC ratio in the presence of naringin decreased by 30% compared to the control group, implying that naringin could be effective to inhibit the metabolism of diltiazem. In conclusion, the concomitant use of naringin significantly enhanced the oral exposure of diltiazem in rats.

Effects of morin pretreatment on the pharmacokinetics of diltiazem and its major metabolite, desacetyldiltiazem in rats

The purpose of this study was to investigate the effect of morin, a flavonoid, on the pharmacokinetics of diltiazem and one of its metabolites, desacetyldiltiazem in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after oral administration of diltiazem (15 mg/kg) in rats pretreated with morin (1.5, 7.5, and 15 mg/kg). Compared with the control group (given diltiazem alone), pretreatment of morin significantly increased the absorption rate constant (Ka) and peak concentration (Cmax) of diltiazem (p<0.05, p<0.01). Area under the plasma concentration-time curve (AUC) of diltiazem in rats pretreated with morin were significantly higher than that in the control group (p<0.05, p<0.01), hence the absolute bioavailability (AB%) of diltiazem was significantly higher than that of the control group (p<0.05, p<0.01). Relative bioavailability (RB%) of diltiazem in rats pretreated with morin was increased by 1.36- to 2.03-fold. The terminal half-life (t1/2) and time to reach the peak concentration (Tmax) of diltiazem were not altered significantly with morin pretreatment. AUC of desacetyldiltiazem was increased significantly (p<0.05) in rats pretreated with morin at doses of 7.5 and 15 mg/ kg, but metabolite-parent ratio (MR) of desacetyldiltiazem was decreased significantly (p<0.05), implying that pretreatment of morin could be effective to inhibit the CYP 3A4-mediated metabolism of diltiazem. There were no apparent changes of Tmax and t1/2 of desacetyldiltiazem with morin pretreatment. Collectively, the pretreatment of morin significantly altered pharmacokinetics of diltiazem, which can be attributed to increased intestinal absorption as well as reduced first-pass metabolism. Based on these results, dose modification should be taken into consideration when diltiazem is used concomitantly with morin or morin-containing dietary supplements in clinical setting.

Pharmacokinetic interaction between diltiazem and morin, a flavonoid, in rats

The present study aims to investigate the effect of morin, a flavonoid, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after an oral administration of diltiazem (15 mg kg −1) to rats in the presence and absence of morin (1.5, 7.5 and 15 mg kg −1). Compared to the control given diltiazem alone, the C max and AUC of diltiazem increased by 30–120% in the rats co-administered with a 1.5 or 7.5 mg kg −1 of morin, while there was no significant change in T max and terminal plasma half-life ( T 1/2) of diltiazem in the presence of morin. Consequently, absolute and relative bioavailability values of diltiazem in the rats co-administered with morin were significantly higher ( p < 0.05) than those from the control group. Metabolite-parent AUC ratio in the presence of morin (7.5 mg kg −1) decreased by 30% compared to the control group, implying that coadministration of morin could be effective to inhibit the CYP3A4-mediated metabolism of diltiazem. In conclusion, the presence of morin significantly enhanced the oral exposure of diltiazem, suggesting that concurrent use of morin or morin-containing dietary supplement with diltiazem should require close monitoring for potential drug interactions.

The influence of cimetidine on the pharmacokinetics of diltiazem and its main metabolite in rabbits.

The purpose of this study was to investigate the pharmacokinetic alteration of diltiazem and its main metabolite, deacetyldiltiazem, after oral administration of diltiazem in rabbits with or without cimetidine co-administration. The area under the plasma concentration-time curve (AUC) of diltiazem was significantly elevated in rabbits pretreated with cimetidine, suggesting that the oral clearance, an index of intrinsic clearance, may be decreased by the cimetidine treatment. Consistent with the increased AUC by the treatment, peak plasma concentration (Cmax) for diltiazem was also elevated. Apparent volume of distribution normalized by the bioavailability (Vd/F) of diltiazem increased significantly in rabbits pretreated with cimetidine increased. Taken together with the fact that the first pass metabolism for diltiazem is the primary determinant for the oral bioavailability, these observations indicate that increases in the oral clearance and Vd/F may be a manifestation of the decreased first pass metabolism. Consistent with the hypothesis, the AUC of deacetyldiltiazem was significantly decreased in rabbits with cimetidine treatment. Ratio of deacetyldiltiazem to total diltiazem in the plasma was significantly decreased in rabbits with cimetidine treatment. These observations suggested that the metabolism of diltiazem to deacetyldiltiazem was reduced by cimetidine treatment and that the dosage of diltiazem should be adjusted when the drug is co-administered chronically with cimetidine in a clinical setting.

Studies on interactions between functional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extract on the pharmacokinetics of diltiazem in rats.

The effects of Ginkgo biloba leaf extract (GBE), one of the most widely used herbal dietary supplements in Japan, on the pharmacokinetics of diltiazem (DTZ), a typical probe of cytochrome P450 (CYP) 3A, were examined in rats. The simultaneous addition of GBE to small intestine and liver microsomes inhibited the formation of N-demethyl DTZ (MA), an active metabolite of DTZ produced by CYP3A, in a concentration-dependent manner, with an IC(50) of about 50 and 182 microg/ml, respectively. This inhibition appeared to be caused, at least in part, by a mechanism-based inhibition. Both the rate of formation of MA and total amount of CYP in intestinal or hepatic microsomes after a single oral pretreatment with GBE (20 mg/kg) decreased transiently. The pretreatment significantly decreased the terminal elimination rate constant and increased the mean residence time, after intravenous administration of DTZ (3 mg/kg). Furthermore, it significantly increased the area under the concentration-time curve and absolute bioavailability after oral administration of DTZ (30 mg/kg). These results indicated that the concomitant use of GBE in rats increased the bioavailability of DTZ by inhibiting both intestinal and hepatic metabolism, at least in part, via a mechanism-based inhibition for CYP3A.

가토에서 딜티아젬과 시메티딘과의 약물상호작용

Diltiazem inhibits calcium channels and Ieads to vascular smooth muscle relaxation and negative inotropic and chronotropic effects in the heart. Diltiazem is almost completely absorbed after oral administration, but its extent of absolute oral bioavailability is reduced because of considerable first-pass hepatic metabolism. Diltiazem is able to dilate renal vasculature and can increase the glomerular filtration rate and renal sodium excretion. The purpose of this study was to report the pharmacokinetic changes of diltiazem after oral administration of diltiazem, 20 mg/kg, in rabbits coadministered with cimetidine, 20 mg/kg and pretreated twice per day for 3 days at cimetidine dose of 20 mg/kg. The area under the plasma concentration-time curve (AUC) of diltiazem was significantly higher in rabbits pretreated with cimetidine than that in control rabbits (p and elimination half-life of diltiazem were increased significantly (p

Pharmacokinetic changes of diltiazem and desacetyldiltiazem after oral administration of diltiazem in rabbits with diabetes mellitus induced by alloxan

Pharmacokinetic changes of diltiazem and desacetyldiltiazem after oral administration of diltiazem in rabbits with diabetes mellitus induced by alloxan

Pharmacokinetics of diltiazem and its major metabolite, deacetyidiltiazem after oral administration of diltiazem in mild and medium folate-induced renal failure rabbits.

The pharmacokinetic changes of diltiazem (DTZ) and its main metabolite, deacetyldiltiazem (DAD) were studied after oral administration of DTZ to normal rabbits and mild and medium folate-induced renal failure rabbits. DTZ 10 mg/kg was given to the rabbits either orally (n=6). Plasma concentrations of DTZ and DAD were determined by a high performance liquid chromatography assay. The area under the plasma concentration-time curves (AUC) and maximum plasma concentration (Cmax) of DTZ were significantly increased in mild and medium folate-induced renal failure rabbits. The metabolite ratio of the DTZ to DAD were significantly decreased in mild and medium folate-induced renal failure rabbits. The volume of distribution (Vd) and total body clearance (CLt) of DTZ were significantly decreased in mild and medium folate-induced renal failure rabbits. The elimination rate constant (beta) of DTZ was significantly decreased in folate-induced renal failure rabbits, but that of DAD was significantly increased. These findings suggest that the hepatic metabolism of DTZ was inhibited and the Vd, CLt and beta of DTZ were significantly decreased in mild and medium folate-induced renal failure rabbits.

Effects of diltiazem on myocardial perfusion abnormalities during exercise in patients with hypertrophic cardiomyopathy.

The effect of diltiazem on myocardial ischemia in patients with hypertrophic cardiomyopathy (HCM) was evaluated by exercise myocardial 201Tl single photon emission computed tomography (SPECT). Exercise myocardial SPECT was performed before and 8 weeks after oral administration of diltiazem (180 mg/day) in 20 patients with HCM who showed transient perfusion defects on exercise myocardial 201Tl SPECT under control conditions. SPECT images were divided into 17 segments. The 201Tl perfusion defects were visually scored and evaluated as the defect score. The transient dilation index was calculated as an index of subendocardial ischemia. Improvement of the defect score was demonstrated in 15 patients after the administration of diltiazem. The mean defect score decreased significantly from 9.90 +/- 5.17 to 5.50 +/- 4.89 (p < 0.0001). Although 16 of 20 patients showed an abnormal transient dilation index before diltiazem treatment, 16 showed improvement and 13 of these normalized after diltiazem therapy. The mean transient dilation index decreased from 1.16 +/- 0.10 to 1.02 +/- 0.09 (p < 0.0001). In conclusion, diltiazem prevents or diminishes myocardial ischemia in patients with HCM.

Simultaneous determination of diltiazem and quinidine in human plasma by liquid chromatography

A novel method for simultaneous determination of diltiazem and quinidine in human plasma is described. Plasma is alkalinized and extracted with methyl tert.-butyl ether. The ether phase is separated and evaporated. The residue is reconstituted in 0.2 ml of mobile phase containing 56 m M octanesulfonic acid then washed twice with n-hexane. Aliquots are chromatographed on a silanol-deactivated reversed-phase column using a mobile phase containing aqueous H 2SO 4 (0.01 M, pH 2)-methanol-acetonitrile (45:45:10) and 10 m M octanesulfonic acid. Peaks are monitored with a UV detector set at 237 nm and a fluorescence detector using an excitation set at 247 nm and a 270 nm UV cut-off filter at the emission. Calibration and standard curves were linear from 1 to 130 ng on-column for diltiazem and from 2 to 600 ng on-column for quinidine. Limits of quantitation were 2 and 4 ng/ml for diltiazem and quinidine, respectively. Recoveries from spiked plasma were 94.0 to 102.5% (R.S.D. 6.0–11.4%) for diltiazem and 98.5% to 104.1 (R.S.D. 7.7–8.7%) for quinidine over the ranges studied. In vitro stability was studied in spiked plasma samples stored at −80°C for sixteen months. Both diltiazem and quinidine remained within 10% from nominal values. For ex vivo stability at −80°C, a plasma sample obtained from a volunteer 2 h after oral administration of diltiazem (60 mg) was analysed for two days after sampling and eighteen months later. The mean deviation from initial measured was 4.7%.

Disparate effects of insulin reduction with diltiazem on serum dehydroepiandrosterone sulfate levels in obese hypertensive men and women.

Evidence suggests that amelioration of hyperinsulinemic insulin resistance in men with calcium channel blockers of the dihydropyridine class is associated with a fall in serum insulin and a rise in serum dehydroepiandrosterone sulfate (DHEA-S) concentrations. The present study was conducted to determine whether 1) the nondihydropyridine calcium channel blocker diltiazem also reduces circulating insulin levels in humans, and 2) a reduction in circulating insulin with a calcium channel blocker is associated with a rise in serum DHEA-S concentrations in women as well as men. Ten obese hypertensive men and 13 obese hypertensive postmenopausal women were studied. Subjects were assessed at baseline and after the oral administration of diltiazem (60 mg, three times daily) for 18 days. Diltiazem treatment was associated with reductions in fasting serum insulin levels in both the men (from 91 +/- 14 to 56 +/- 12 pmol/L; P < 0.03) and women (from 92 +/- 20 to 48 +/- 9 pmol/L; P = 0.05). Serum glucose levels did not change in either group. In men, concurrent with the fall in serum insulin levels, serum DHEA-S levels rose from 4.05 +/- 1.06 to 6.91 +/- 1.32 mumol/L (P < 0.04), and serum DHEA levels rose from 14.4 +/- 3.0 to 24.3 +/- 4.6 nmol/L (P = 0.05) with diltiazem treatment, whereas serum cortisol did not change. In contrast, diltiazem administration in the women was not associated with any change in serum DHEA-S, DHEA, or cortisol levels. These observations suggest that the action of calcium channel blockers to lower fasting serum insulin levels is not specific for the dihydropyridine class and applies to both men and women. Furthermore, the finding of a sex-based disparity in DHEA-S and DHEA responses to insulin reduction suggests that the metabolism of these steroids may be regulated differently in men than in women.

Hypotensive response of spontaneously hypertensive rats to centrally administered diltiazem and its metabolites: in relevance to the hypotensive action by oral administration.

In order to study whether a part of the antihypertensive action of orally administered diltiazem is mediated by the central nervous system and whether metabolites of diltiazem contribute to the actions of diltiazem, we compared the effects of diltiazem and its main metabolites on blood pressure by intravenous administration with those by intracerebroventricular administration to spontaneously hypertensive rats (SHR). Contents of diltiazem and its metabolites in the brain of SHR after oral administration were also studied. Hypotensive action of intravenously administered diltiazem was stronger than that of its main metabolites in terms of potency and durability. Diltiazem (30 micrograms or more) and its main metabolites (100 micrograms) showed weak hypotensive action by intracerebroventricular administration. Oral administration of diltiazem (30 mg/kg) decreased mean blood pressure by about 40 mmHg 30 min after the administration. At this time, contents of unchanged form and metabolites of diltiazem in the brain were 0.78 +/- 0.10 and 7.58 +/- 0.89 micrograms/whole brain, respectively. It was suggested that hypotensive action of diltiazem was mainly attributable to the unchanged form and that the contribution of central action to the acute hypotensive action of diltiazem was unlikely, although centrally administered diltiazem can cause systemic hypotension.