• Archives of Pharmacal Research
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• v.27 no.2
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• pp.254-258
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• 2004

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 with-out 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 ($C_{max}$) for diltiazem was also elevated. Apparent volume of distribution normalized by the bioavailability (($V_{d}$/F) of diltiazem increased sigrificantly 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 (($V_{d}$/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.

• Korean Journal of Clinical Pharmacy
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• v.10 no.3
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• pp.120-124
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• 2000

Diltiazem inhibits calcium channels and leads to vascular smooth muscle relaxation and negative inotroic and chronotropic effects in the heart. Diltiazem (DTZ) is almost completely absorbed after oral administration, but its bioavailability is reduced because of considerable hepatic first-pass metabolism. The main metabolite of DTZ is deacetyldiltiazem. The purpose of this study was to report the pharmacokinetic changes of DTZ and its metabolite, deacetyldiltiazem (DAD) after intravenous administration of diltiazem to control rabbits and rabbits with mild and medium folate-induced renal failure (FIRRs). The area under the plasma concentration-time curves (AUC) of DTZ were significantly increased in mild and medium FIRRs. The metabolite ratio of the DAD to DTZ were significantly decreased in mild and medium FIRRs. The elimination rate constant $(\beta)$ and total body clearances (CLt) of DTZ were significantly decreased in mild and medium FIRRS. These findings suggest that the hepatic metabolism of diltiazem was inhibited and CLt and ${\beta}$ of DTZ were significantly decreased in mild and in rabbits with medium folate-induced renal failure.

• YAKHAK HOEJI
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• v.49 no.3
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• pp.230-236
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• 2005

The purpose of this study was to investigate the effect of naringin pretreatment on the bioavailability and phar-macokinetics of diltiazem and one of its metabolites, deacetyldiltiazem, in rabbits. Pharmacokinetic parameters of diltiazem and deacetyldiltiazem were determined after oral administration of diltiazem (15 mg/kg) pretreated with naringin (1.5, 7.5 and 15 mg/kg). Absorption rate constant ($k_a$) of diltiazem after oral administration of diltiazem pretreated with naringin was significantly (p<0.05 or p<0.0l) increased compared to the control group. Area under the plasma concentration-time curve (AUC) and peak concentration ($C_{max}$) of the diltiazem were significantly (p<0.05 or p<0.01) higher than those of the control. Absolute bioavailability ($AB\%$) of diltiazem pretreated with naringin ranged from $13.5\%$ to $18.6\%$, being enhanced compared to that of the control, $7.2\%$. Relative bioavailability ($RB\%$) of diltiazem was $1.9\~2.6$ times higher than that of the control group. There was no significant change in terminal half-life ($t_{1/2}$) and $T_{max}$ of diltiazem in the presence of naringin. AUC of deacetyldiltiazem pretreated with naringin was significantly (p<0.05) higher than (p<0.05) that of the control. But the metabolite ratios (MR) were significantly decreased (p<0.05), implying that pretreatment of naringin could be effective to inhibit the CYP 3A4-mediated metabolism of diltiazem. In this study, pretreatment of naringin significantly enhanced the oral bioavailability of diltiazem. These results suggested that the diltiazem dosage should be adjusted when it is administered with naringin or a naringin-containing dietary supplement in the clinical setting.

• Journal of Pharmaceutical Investigation
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• v.22 no.4
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• pp.317-321
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• 1992

A high-performance liquid chromatographic (HPLC) method was developed for the determination of diltiazem (DTZ) and its major metabolite, deacetyldiltiazem (DAD), in rat plasma. DTZ, DAD and imipramine, the internal standard, were selectively fractionated from plasma on a $C_{18}$ reversedphase column $({\mu}-Bondapak,\;10\;{\mu}m\;silica,\;300{\times}3.9\;mm\;ID)$. The composition of the mobile phase was methanol: acetonitrile: 0.04 M ammonium bromide: triethylamine (40:24:36:0.06 in volume). The pH of the mobile phase of their method was lowered to 6.4. The eluents from the column were detected for DTZ and DAD using a UV detector at 237 nm. The recovery was >85% for DTZ and DAD, and average intra-day and inter-day coefficients of variation were <6% for DTZ and DAD at the concentration ranges of 20-1000 ng/ml. Detection limit of DTZ and DAD in plasma was 20 ng/ml with signal-to-noise ratio of 3. This method would be applicable to practical pharmacokinetic studies without detriment to the HPLC column.

• Archives of Pharmacal Research
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• v.24 no.4
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• pp.333-337
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• 2001

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 ($C_{max}$) 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 ($V_{d}$) and total body clearance ($CL_{t}$) 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 $V_{d}$, $CL_{t}$ and $\beta$ of DTZ were significantly decreased in mild and medium folate-induced renal failure rabbits.

• Proceedings of the PSK Conference
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• 2000.10a
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• pp.275.1-275.1
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• 2000