Oxidation of nilvadipine, a new dihydropyridine calcium antagonist, to the corresponding pyridine by rat liver microsomes

1. The oxidation of nilvadipine, a 1,4-dihydropyridine derivative, by rat liver microsomes and sex-related differences in this activity were investigated. 2. The kinetic data (Km and Vmax) for the formation of the corresponding pyridine analogue by liver microsomes from adult male rat (7 weeks old) were similar to those for the disappearance of nilvadipine, indicating that the aromatization of nilvadipine is the primary metabolic step. 3. The formation of the pyridine analogue required the presence of NADPH-generating system and was significantly inhibited by cytochrome c, metyrapone, and 7,8-benzoflavone, indicating the participation of cytochrome P-450. Phenobarbital pretreatment of rats caused an increase in the metabolism of nilvadipine. 4. Nilvadipine oxidase activity in adult male rat was about 10 times higher than that in adult female rat. In contrast, marked sex-related differences were not seen in immature rat (21 days old), and the activity was approximately twice as high as that in adult female rat. No activity was detected in the postmitochondrial fractions of lung, kidney, brain, heart, pancreas or small intestine of adult male rat.     

Metabolism of nilvadipine, a new dihydropyridine calcium antagonist, in rats and dogs

1. The metabolic profiles of nilvadipine in the excreta of male rats and dogs were studied after i.v. and oral dosing. Six types of metabolites were isolated and identified from the urine of male rats and dogs or bile of rats. 2. Several metabolites were detected in the urine (12) and bile (17) of rats by two-dimensional t.l.c., after dosing with 14C-nilvadipine. The metabolic profiles in the excreta of rats and dogs were qualitatively similar but quantitative differences were observed. 3. The main metabolites were products of (i) oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine, (ii) hydrolysis of the 5-isopropyl ester or 3-methyl ester group to carboxylic acid, and/or (iii) hydroxylation of the 6-methyl group or methyl group of the isopropyl ester chain. 4. Minor metabolites were products of hydrolysis from the 5-isopropyl ester to the carboxylic acid having a dihydropyridine ring, or reduction of the 3-nitro group of the phenyl moiety having a pyridine ring.     

Metabolism of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The metabolic profiles of nilvadipine in the excreta of male rats and dogs were studied after i.v. and oral dosing. Six types of metabolites were isolated and identified from the urine of male rats and dogs or bile of rats.

2. Several metabolites were detected in the urine (12) and bile (17) of rats by two-dimensional t.l.c., after dosing with ¹⁴C-nilvadipine. The metabolic profiles in the excreta of rats and dogs were qualitatively similar but quantative differences were observed.

3. The main metabolites were products of (i) oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine, (ii) hydrolysis of the 5-isopropyl ester or 3-methyl ester group to carboxylic acid, and/or (iii) hydroxylation of the 6-methyl group or methyl group of the isopropyl ester chain.

4. Minor metabolites were products of hydrolysis from the 5-isopropyl ester to the carboxylic acid having a dihydropyridine ring, or reduction of the 3-nitro group of the phenyl moiety having a pyridine ring.     

Absorption,distribution and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of ¹⁴C-nilvadipine.

2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4–3.5% in rats and 10.4–22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8–10h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs.

3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys.

4. With both routes of dosing, urinary excretion of radioactivity was 21–24% dose in rats and 56–61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.     

Pharmacokinetics of nilvadipine, a new dihydropyridine calcium antagonist, in mice, rats, rabbits and dogs

1. The pharmacokinetics of nilvadipine in male and female rats, and in male mice, rabbits and dogs were studied after i.v. and oral dosing. 2. After i.v. dosing (0.1 mg/kg), the plasma concentrations of nilvadipine declined two- or three-exponential with terminal half-lives of 0.73 h in mice, 1.2 h in male and female rats, 3.7 h in rabbits and 5.0 h in dogs. Sex difference in pharmacokinetics after i.v. dosing in rats was not found. The systemic plasma clearance was in the order of mice greater than rats greater than rabbits greater than dogs, and nearly equalled the hepatic blood flow in each species. The volume of distribution at steady-state was high (greater than 4 L/kg) in all species. 3. After oral dosing, plasma concentrations of nilvadipine peaked within 1 h in all species except for middle and higher doses (4 and 16 mg/kg) in dogs. The area under the plasma concentration-time curves in male rats (3.2-100 mg/kg) and dogs (1-16 mg/kg) increased in proportion to the dose. Bioavailability was low in male rats (3-4%) and rabbits (2%), but in other species was 29-44%. The oral clearance in male rats was about 8 times higher than in female rats. 4. The free fraction of nilvadipine in plasma was 1.94% in mice, 1.89% in rabbits and 0.85% in dogs, with no dependence on plasma concentration over a range of 10-100 ng/ml.     

Sex differences in the metabolism and excretion of nilvadipine, a new dihydropyridine calcium antagonist, in rats

1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1 mg/kg of the 14C-labelled compound. 2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48 h were 84.1% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces. 3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with 14C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats. 4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24 h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.     

Sex differences in the metabolism and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats

1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1?mg/kg of the ¹⁴C-labelled compound.

2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48?h were 8.41% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces.

3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with ¹⁴C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats.

4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24?h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.     

Absorption, distribution and excretion of lacidipine, a dihydropyridine calcium antagonist, in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog). 2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism. 3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug. 4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species. 5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses. 6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration. 7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Absorption,distribution and excretion of lacidipine,a dihydropyridine calcium antagonist,in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog).

2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism.

3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug.

4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species.

5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses.

6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration.

7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Antihypertensive effects of a new dihydropyridine calcium antagonist

Methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2 -yl)-1,4-dihydropyridine-3-carboxylate (DHP-218) is a new vasodilatory calcium antagonist with pronounced and long-lasting antihypertensive effects. It produced a significant decrease in blood pressure at doses more than 1 mg/kg in normotensive rats, 0.1 mg/kg in spontaneously hypertensive rats (SHR) and desoxycorticosterone acetate (DOCA)-salt hypertensive rats and 0.3 mg/kg in renal hypertensive rats. In SHR, the antihypertensive effect of DHP-218 was approximately 7 times more potent than nifedipine. The antihypertensive effect of DHP-218 appeared very slowly and persisted even after it was injected i.v. No tolerance to the antihypertensive effects of DHP-218 was observed for 5 weeks at daily doses of 0.3 and 1 mg/kg. The antihypertensive effects of DHP-218 in cats and dogs with normal blood pressure was more than 10 and 30 times more potent than those of nifedipine, respectively. At an equivalent antihypertensive dose, the effect of DHP-218 persisted longer than that of nifedipine in all the animal species used.     

Cardiovascular effects of a new dihydropyridine calcium antagonist

The effects of methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo- 1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate (DHP-218), a 1,4-dihydropyridine derivative, on the cardiovascular system and myocardial oxygen consumption were investigated. Effects on cardiovascular system: In urethane-alpha-chloralose anesthetized dogs, DHP-218 at a dose of 0.01 mg/kg i.v. decreased blood pressure (BP), and at 0.03 mg/kg i.v., long-lasting BP decrease was accompanied by an increase in heart rate (HR), and an increase in blood flow of the coronary, vertebral and internal carotid arteries. No significant changes in myocardial contractile force (MCF) and blood flow of the common carotid and renal arteries were observed. The duration of action was different for various effects. At doses more than 0.05 mg/kg i.d., blood pressure decreased and HR, MCF and the blood flow of coronary and vertebral arteries increased. The effects of nifedipine on the cardiac and regional blood flow were observed at doses more than 0.001 mg/kg i.v. and 1 mg/kg i.d., but the duration of its action was very short compared to those of DHP-218. Effects on cardiohemodynamics: In urethane-alpha-chloralose anesthetized dogs, DHP-218 at a dose of 0.01 mg/kg i.v. produced a decrease in BP and total peripheral resistance (TPR) and an increase in cardiac output (CO). At a dose of 0.03 mg/kg, a decrease in BP and TPR and increases in HR and CO were observed. The duration of action was different for various parameters. No significant changes in dp/dtmax, stroke volume and cardiac work were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of nilvadipine, a dihydropyridine calcium antagonist, on cytochrome P450 activities in human hepatic microsomes

The effects of nilvadipine, a dihydropyridine calcium antagonist, on cytochrome P450 (CYP) activities in human hepatic microsomes were investigated. Nilvadipine competitively inhibited CYP1A2-mediated 7-ethoxyresorufin O-deethylase, CYP2A6-mediated coumarin 7-hydroxylase, CYP2C8/9-mediated tolbutamide methylhydroxylase, CYP2C19-mediated S-mephenytoin 4'-hydroxylase, and CYP3A4-mediated nifedipine oxidase activities, and the inhibition constant (Ki) values were 13.0, 35.8, 5.02, 24.5 and 44.3 microM, respectively. On the other hand, no inhibition of CYP2B6-mediated 7-benzyloxyresorufin O-debenzylation, CYP2D6-mediated bufuralol 1'-hydroxylation, or CYP2E1-mediated chlorzoxazone 6-hydroxylation by nilvadipine at 40 microM concentration was observed. The free fractions of nilvadipine in the incubation mixture estimated by ultracentrifugation were 18.9-27.4%. These results suggest that nilvadipine would not cause clinically significant interactions with other drugs, which are metabolized by CYPs, via the inhibition of metabolism.     

Interaction potential of lercanidipine, a new vasoselective dihydropyridine calcium antagonist

Using some calcium channel blockers of the dihydropyridine-type (amlodipine (CAS 88150-42-9, felodipine (CAS 72508-76-3), lercanidipine (CAS 100472-26-7), nifedipine (CAS 21829-25-4), nitrendipine (CAS 39562-70-4)) as example the interaction potential of these substances will be compared in terms of affecting metabolism and transport of drugs. The cytochrome P450 (CYP) isoform CYP3A4 and the P-glycoprotein (P-gp), respectively, will have a high impact for both pharmacokinetic processes, as all 5 calcium channel blockers are substrates of CYP3A4 and in addition nifedipine, nitrendipine and felodipine represent inhibitors of P-gp, which can cause an increase in the plasma levels of digoxin (model substrate of P-gp). If inducers (e.g. rifampicin, anticonvulsants, St John's wort) or inhibitors (ketoconazole, itraconazole, erythromycin, clarithromycin, nefazodone, fluvoxamine, fluoxetine, sertraline, ritonavir, indinavir, amprenavir, saquinavir or grapefruit juice) of CYP3A4 are concomitantly administered pharmacokinetic interactions could be expected to a variable extent. Some alternative drugs are mentioned which will not affect CYP3A4. In addition to these putative pharmacokinetic interactions also pharmacodynamic interactions with other cardiovascular active substances might be considered and some caution should be exercised if vasodilators are given as comedication.     

Metabolism of a new dihydropyridine calcium antagonist in rats and dogs

1. The metabolism of a new dihydropyridine calcium channel blocker was studied in rats and dogs. The drug was extensively metabolized by both species after oral dosing. Metabolites were detected by two-dimensional t.l.c. after dosing with the ¹⁴C-labelled drug. Urinary metabolite patterns were quantitatively different in rats and dogs.

2. Ten metabolites were isolated from urine, bile and liver homogenate of male or female rats, and identified.

3. The main metabolic pathway was oxidation of the dihydropyridine moiety to the pyridine form, followed by the hydrolysis of the ester, oxidation of the methyl group at the 6-position, and oxidation of the isopropyl group. Other pathways were hydrolysis of the 3-isopropyl ester or 5-methyl ester group to the dihydropyridine monocarboxylic acid (M-2 and M-10, respectively).

4. The drug was metabolized in rats stereoselectively. M-2 and M-10 isolated from rat female urine were analysed by chiral stationary-phase h.p.l.c. and were mainly the enantiomers derived from (-)- and (+)-drug, respectively.     

Metabolism of a new dihydropyridine calcium antagonist in rats and dogs

1. The metabolism of a new dihydropyridine calcium channel blocker was studied in rats and dogs. The drug was extensively metabolized by both species after oral dosing. Metabolites were detected by two-dimensional t.l.c. after dosing with the 14C-labelled drug. Urinary metabolite patterns were quantitatively different in rats and dogs. 2. Ten metabolites were isolated from urine, bile and liver homogenate of male or female rats, and identified. 3. The main metabolic pathway was oxidation of the dihydropyridine moiety to the pyridine form, followed by the hydrolysis of the ester, oxidation of the methyl group at the 6-position, and oxidation of the isopropyl group. Other pathways were hydrolysis of the 3-isopropyl ester or 5-methyl ester group to the dihydropyridine monocarboxylic acid (M-2 and M-10, respectively). 4. The drug was metabolized in rats stereoselectively. M-2 and M-10 isolated from rat female urine were analysed by chiral stationary-phase h.p.l.c. and were mainly the enantiomers derived from (-)- and (+)-drug, respectively.     

Pharmacokinetics of barnidipine hydrochloride,a new dihydropyridine calcium channel blocker,in the rat,dog and human

1. The pharmacokinetics of a new calcium antagonist barnidipine hydrochloride, a stereochemically pure enantiomer, was studied after intravenous and oral dosing to the rat and dog, and oral to man.

2. After intravenous dosing, plasma concentrations of barnidipine hydrochloride declined bi-exponentially with the terminal half-lives of 0·6?h in the rat and 4·1?h in the dog. The blood clearance was 5·21/h/kg in the rat and 3·31/h/kg in the dog, and was comparable with hepatic blood flow in both species.

3. After oral dosing, plasma concentrations of barnidipine hydrochloride peaked rapidly (0·3-0·4?h in the rat and dog, 1·0–1·6?h in man). C_max and AUC rose non-linearly with increasing doses in all three species.

4. The absolute bioavailability was low (11–18% in the rat and 6–9% in the dog), suggesting a marked first-pass metabolism.     

Cardiovascular actions of the dihydropyridine calcium antagonist nimodipine in the dog

When injected i.v. into anaesthetized, open-chest dogs, isopropyl (2-methoxyethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate (nimodipine, Bay e 9736) (0.3-10 micrograms/kg) produced an increase in coronary sinus outflow and decreases in mean arterial blood pressure, coronary resistance, arterio-venous oxygen difference and heart rate in a dose-dependent manner, but virtually no change in myocardial oxygen consumption. At 3 micrograms/kg i.v. of the drug coronary resistance fell nearly to half the pre-drug value, coronary sinus outflow nearly doubled and heart rate decreased by about 10 beats/min. Myocardial oxygen consumption was slightly reduced at 30 micrograms/kg i.v. and atrioventricular (AV) conduction time was slightly increased at 10 and 30 micrograms/kg i.v. of the drugs. When the coronary vascular and cardiac effects of nimodipine were assessed in isolated, blood-perfused dog heart preparations, i.e., sinoatrial node, AV node and papillary muscle preparations, by intra-arterial administration, the following was revealed. In nearly twice the dose doubling coronary arterial blood flow, nimodipine produced a 15% decrease in sinus rate and a 15% increase in AV conduction time. However, in reducing the force of contraction of the papillary muscle by half the pre-drug value was needed nearly 17 times the dose of nimodipine doubling coronary arterial blood flow. Suppression of AV conduction by large doses of nimodipine was evident only when it was injected into the artery supplying the AV node but not into the artery supplying the His-Purkinje-ventricular system.(ABSTRACT TRUNCATED AT 250 WORDS)     

新型的二氢吡啶类钙通道阻滞药乐卡地平的抗高血压作用

乐卡地平是一种新型的二氢吡啶类钙通道阻滞药 ,其亲脂性强 ,对血管平滑肌的舒张作用缓慢、持久、显著 ;动物及临床实验显示其降压作用持久、安全 ,并且对高血压作用的靶器官有保护作用     

Antihypertensive activity of OPC-13340, a new potent and long-acting dihydropyridine calcium antagonist, in rats.

The antihypertensive action of OPC-13340, a new dihydropyridine, was studied in rats and compared with the action of nicardipine and other dihydropyridines. OPC-13340 showed more potent and longer hypotensive action than nicardipine when administered either intravenously (i.v.) or orally in normotensive and hypertensive rats. Among 6 compounds tested, (OPC-13340, nifedipine, nitrendipine, nisoldipine, nicardipine and diltiazem), OPC-13340 was the most potent and long-acting when administered orally to spontaneously hypertensive rats (SHR). Tachycardia after administration of OPC-13340 was less or diminished earlier than that of nicardipine. Oral administration of OPC-13340 (3 mg/kg) once daily for 13 days did not cause any rebound phenomena in SHR. The compound inhibited Ca- or K-induced contractions in isolated rat aorta and shortened action potential duration in guinea pig papillary muscle, suggesting Ca channel blocking action. OPC-13340 might be useful as a drug for once-daily therapy of essential hypertension.     

Ambulatory blood pressure monitoring in elderly hypertensives treated with the new calcium antagonist,nilvadipine

Summary. A newly developed calcium antagonist, nilvadipine, was administered to 7 hypertensive patients aged 75.6 y.Nilvadipine 4 mg b.d. decreased the average 24-h blood pressure significantly from 169/89 mm Hg to 152/81 mm Hg after 7 to 14 days without any change in the pulse rate. The circadian patterns of blood pressure and pulse rate were not affected by nilvadipine.Although the present study was a preliminary one done over a short period in a small number of patients, the results suggest that nilvadipine exerts an antihypertensive effect without altering the circadian pattern or the variability of blood pressure in elderly hypertensive patients.