Effects of lovastatin on the pharmacokinetics of nicardipine in rats.

It has been reported that both nicardipine and lovastatin are substrates of both the cytochrome P450 (CYP) 3A subfamily and P-glycoprotein (P-gp), and P-gp transport is unlikely to be a significant factor. Thus, the effects of oral lovastatin on the pharmacokinetics of intravenous and oral nicardipine were investigated in rats. Nicardipine was administered intravenously (4 mg/kg) and orally (12 mg/kg) with 0 (control), 0.3 and 1 mg/kg of oral lovastatin to rats. Lovastatin was administered 30 min before nicardipine administration. After intravenous administration of nicardipine with 0, 0.3 and 1 mg/kg of lovastatin, the total areas under the plasma concentration-time curve from time zero to infinity (AUCs) of nicardipine were not changed by lovastatin. However, after oral administration of nicardipine with 1 mg/kg of oral lovastatin, the AUC of nicardipine was significantly greater (by 67.4%), and the extent of absolute oral bioavailability (F) of nicardipine was increased (by 38.5%). The above data suggest that lovastatin did not considerably inhibit the metabolism of nicardipine via the hepatic CYP3A subfamily, but inhibited intestinal P-gp and/or the CYP3A subfamily.

Effects of morin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine in rats.

This study investigated the effects of orally administered morin, an inhibitor of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), on the pharmacokinetics of orally and intravenously administered nicardipine in rats. Nicardipine is reportedly a substrate for CYP3A4 and P-gp. Nicardipine was administered orally (12 mgkg(-1)) with or without orally administered morin (1.5, 7.5 and 15 mgkg(-1)), and intravenously (4 mgkg(-1)) with or without orally administered morin (7.5 and 15 mgkg(-1)). In the presence of morin, the pharmacokinetic parameters of nicardipine were significantly altered in the oral group but not in the intravenous group, suggesting that CYP3A-mediated metabolism of nicardipine in the liver is not significantly inhibited by morin. The presence of 7.5 and 15 mgkg(-1) of morin significantly increased (P < 0.01, 67.8-112%) the area under the plasma concentration-time curve and the peak plasma concentration (P < 0.01, 53.5-93.1%) of orally administered nicardipine. The presence of 7.5 and 15 mgkg(-1) of morin significantly decreased (P < 0.01, 40.4-52.8%) the total body clearance of orally administered nicardipine compared with the control group. The enhanced oral bioavailability of nicardipine suggests that intestinal-mediated CYP3A4 metabolism and P-gp-mediated efflux of nicardipine are inhibited by morin. Based on these results, concomitant use of morin or morin-containing dietary supplements with nicardipine may require close monitoring for potential drug interactions.

Reduced prehepatic extraction of nicardipine in the presence of pioglitazone in rats.

This study investigated the effect of pioglitazone on the pharmacokinetics of oral and i.v. nicardipine in rats. Pharmacokinetic parameters were determined after nicardipine was administered orally (12 mg kg(-1)) or i.v. (4 mg kg(-1)) with or without a single dose of oral pioglitazone (0.3 or 1.0 mg kg(-1)). Compared with the control group given nicardipine alone, coadministration of pioglitazone significantly decreased the total plasma clearance of orally administered nicardipine (by 40.4-46.3%, P < 0.05) and significantly increased the area under the plasma concentration-time curve (by 81.8-96.3%) and the peak plasma concentration, C(max) (by 56.5-66.8%). T(max) and the terminal plasma half-life of nicardipine were not affected, however. Coadministration of oral pioglitazone did not affect the pharmacokinetics of i.v. nicardipine, implying that pioglitazone may mainly decrease the prehepatic extraction of nicardipine during intestinal absorption. In conclusion, pioglitazone significantly enhanced the oral bioavailability of nicardipine in rats by reducing its presystemic clearance.

Rifampicin reverses nicardipine effect inducing uncontrolled essential hypertension.

Dihydropyridine calcium-channel blockers are a known substrate for the cytochrome P450 isoform 3A4. Rifampicin, an antitubercular agent, is one of the most potent inducers of hepatic and intestinal CYP3A4 thus increasing dihydropyridine metabolism. We report a case of a 67-year-old hypertensive female treated with a four-drug antihypertensive regimen including a dihydropyridine (nicardipine 50 mg bid), who was admitted for septic arthritis of the knee requiring antibiotic treatment with teicoplanin 400 mg od and rifampicin 600 mg bid. Six days after rifampicin initiation, she presented with Posterior Reversible Encephalopathy Syndrome due to uncontrolled hypertension. We hypothesized that disequilibrium of previously controlled hypertension was partially due to nicardipine ineffectiveness. Plasma nicardipine concentration was assessed through high-performance liquid chromatography 5 hours after coadministration of the two drugs and proved undetectable.

Liquid chromatography-mass spectrometry method for the determination of nicardipine in human plasma.

A simple and sensitive liquid chromatography-mass spectrometry method is described for the determination of nicardipine in human plasma. Chromatographic separation of the analyte was achieved on a C(18) column using a mobile phase of methanol, water and formic acid (320:180:0.4, v/v/v). Selected ion monitoring (SIM) in positive mode was used for analyte quantification at m/z 480.2 for nicardipine and m/z 256.4 for diphenhydramine. The run time was less than 5 min. The linearity over the concentration range of 0.05-20.0 ng/ml for nicardipine was obtained and the lower limit of quantification was 0.05 ng/ml. For each level of QC samples, inter-day and intra-day precisions (R.S.D.) were < or =9.3 and 11.1%, respectively, and accuracy (RE) was +/-4.9%. The present LC-MS method was successfully applied in the pharmacokinetic studies of nicardipine hydrochloride delayed-release tablets in two formulations after oral administration to healthy volunteers.

Intravenous nicardipine for the treatment of severe hypertension. A double-blind, placebo-controlled multicenter trial.

A placebo-controlled, double-blind multicenter trial was conducted in 123 patients with severe hypertension to examine the efficacy and safety of intravenously administered nicardipine hydrochloride in controlling blood pressure. Seventy-three patients were initially randomized to receive nicardipine treatment. This group had an initial blood pressure of 213 +/- 3/126 +/- 2 mm Hg. Sixty-seven patients achieved the therapeutic goal (diastolic blood pressure less than or equal to 95 mm Hg; systolic blood pressure less than or equal to 160 mm Hg). Fifty patients were randomized to receive placebo solution. Blood pressure in these patients was 216 +/- 3/125 +/- 2 mm Hg. No patient in this group achieved the therapeutic goal during the "blinded" portion of the study. Forty-four of 49 patients who did not respond to placebo administration responded to subsequent treatment with nicardipine. Patients with end-organ damage were included in the study. These included patients with left ventricular hypertrophy, retinopathy, and renal insufficiency. Patients with and without end-organ damage responded equally well to nicardipine treatment. Serious adverse experiences were infrequent, the most common adverse reaction being headache in 24% of the patients studied.

[Toxicological analysis of selected 1,4-dihydropyridine calcium channel blockers in the diagnosis of intoxications]. / Analiza toksykologiczna wybranych pochodnych 1,4-dihydropirydyny w diagnostyce zatruc.

This study is aimed at evaluating effective techniques of qualitative and quantitative analysis of selected 1,4-dihydropyridine calcium channel blockers, useful both for thanatological diagnosis of intoxications as well as monitoring therapy. The studies took advantage of gas chromatography (GLC) and high performance liquid chromatography (HPLC). Isolation of studied compounds from biological material was performed using classical and solid phase extraction procedures (SPE) such as Bond Elut LRC (Varian), Abselut Nexus (Varian), STRATA C - 18 E (Phenomenex). The program included analysis of nine of the most frequently prescribed derivatives: nifedipine, felodipine, amlodipine, nicardipine, nimodypine, nilvadipine, nitrendipine, nisoldipine, isradipine.

The effect of hepatic cirrhosis on the pharmacokinetics and blood pressure response to nicardipine.

The present study was designed to compare the pharmacokinetic handling of a single oral dose of nicardipine in normal subjects and in patients with hepatic cirrhosis and to compare the sensitivity of the two groups to its hypotensive effect. Nicardipine plasma concentrations were substantially higher in the subjects with hepatic cirrhosis with impaired antipyrine clearance, as shown by a significantly higher average Cmax and AUC. The terminal elimination half-life in this group varied from 0.8 to 60.2 hours (median, 11.7 hours), compared with 0.6 to 4.1 hours (median, 1.4 hours) in the group of eight subjects with normal liver function. In the cirrhotic patients with impaired antipyrine clearance, the AUC of the pyridine metabolite averaged 10% of that of the parent drug, whereas in normal subjects the ratio averaged 48%. This finding suggests less conversion of nicardipine to this metabolite in subjects with impaired hepatic function. Peak blood pressure decreases were greater in the cirrhotic group, which was in keeping with the higher plasma levels in these subjects.

Serum concentrations and effects of (+/-)-nicardipine compared with nifedipine in a population of healthy subjects.

The dihydropyridine calcium antagonist (+/-)-nicardipine shares some of the pharmacologic properties of the dihydropyridine prototype nifedipine. To compare them, serum concentrations and cardiovascular effects of 10 mg nifedipine and 20 mg (+/-)-nicardipine were evaluated at 1, 2, and 3 hours after oral intake in a randomized, crossover, single-blind study involving 79 healthy volunteers. (+/-)-Nicardipine serum concentrations were much lower than those of nifedipine, indicating a greater hepatic first-pass metabolism of (+/-)-nicardipine. There was a significant correlation between serum concentrations of both drugs. The frequency distributions of nifedipine and (+/-)-nicardipine AUC (0-3), heart rate increase, and mean arterial pressure decrease showed no bimodality. This does not confirm the proposed polymorphism of nifedipine oxidation. Concentration-effect plots indicate that (+/-)-nicardipine is more potent than nifedipine but shows comparable efficacy in blood pressure reduction.

Antihypertensive effects of parenteral nicardipine alone and in combination with captopril.

We studied the safety and efficacy of intravenous nicardipine alone and in combination with oral captopril. Sixteen patients with essential hypertension received a single oral dose of captopril, 50 mg, to be certain that excessive hypotension would not occur. Nicardipine was given intravenously as a 2 mg bolus, followed by an infusion at a rate designed to lower the supine diastolic blood pressure at least 10 mm Hg; then oral captopril, 50 mg, or placebo was given. The next week, nicardipine was again infused, but the alternate oral treatment was given. Intravenous nicardipine reduced blood pressure from 156 +/- 15/101 +/- 5 mm Hg (mean arterial blood pressure 120 +/- 6 mm Hg) to 140 +/- 11/88 +/- 4 mm Hg (mean arterial blood pressure 105 +/- 5 mm Hg). When captopril was added to nicardipine, the mean arterial blood pressure fell an additional 8 mm Hg but the heart rate did not increase. The combination of angiotensin-converting enzyme inhibition and calcium channel blockage produces additive antihypertensive effects without additional reflex tachycardia.

Intravenous nicardipine for the treatment of severe hypertension.

PURPOSE: Severe hypertension responds to treatment with nifedipine given orally or sublingually. Nicardipine hydrochloride, a water soluble dihydropyridine analogue similar to nifedipine, has less of a negative ionotropic effect and produces less reflex tachycardia than nifedipine. Our purpose was to assess the antihypertensive efficacy and safety of intravenous nicardipine in a group of patients with severe hypertension (defined as a supine diastolic blood pressure of more than 120 mm Hg). PATIENTS AND METHODS: Eighteen patients with severe hypertension received treatment with intravenous nicardipine. Nicardipine titration was performed using doses of 4 to 15 mg/hour to achieve therapeutic goal (diastolic blood pressure 95 mm Hg or less or decrease in diastolic blood pressure of more than 25 mm Hg). After this therapeutic end-point was reached, patients received maintainance therapy with nicardipine for varying lengths of time: one hour (Group I), six hours (Group II), or 24 hours. When blood pressure control was lost, patients in Groups I and II entered a second maintenance period lasting a maximum of 24 hours. Onset and offset of action of nicardipine at various infusion rates and times of infusion were measured. RESULTS: Onset time to achieve therapeutic response was rapid at 15 mg/hour (0.31 +/- 0.13 hours) when compared with lower doses (1.11 +/- 0.36 hours at 4 mg/hour; 0.54 +/- 0.09 hours at 5 mg/hour; 0.52 +/- 0.09 hours at 7 to 7.5 mg/hour). Those who showed a therapeutic response received maintenance infusions with nicardipine for one (n = 7), six (n = 6), or 24 (n = 5) hours. Sustained blood pressure control at a constant rate of nicardipine infusion was seen in all patients during the maintenance period. After discontinuation of nicardipine, the time for offset of action (increase in diastolic blood pressure of 10 mm Hg or more) was independent of duration of infusion. Decreases in both systolic and diastolic pressures correlated well with plasma nicardipine levels. Heart rate increased by about 10 beats/minute, but this increase did not correlate with plasma nicardipine levels. Side effects were minimal, consisting of headache and flushing. In seven patients, local phlebitis developed at the site of infusion. This occurred after at least 14 hours of infusion at a single site, and the incidence can probably be reduced by shortening the infusion time at a single site. CONCLUSION: Nicardipine appears to be a safe and effective drug for intravenous use in the treatment of severe hypertension.

Evaluation of slow release nicardipine in essential hypertension by casual and ambulatory blood pressure measurements. Effects of acute versus chronic administration.

We conducted a randomized placebo-controlled double-blind study in 40 hypertensive subjects to assess the antihypertensive effect of a new galenic form of nicardipine administered at a dosage of 50 mg twice daily for 3 weeks. Regardless of whether blood pressure was measured by standard mercury sphygmomanometer, non-ambulatory automatic oscillometry or a Remler ambulatory blood pressure recorder, it dropped by a significantly larger amount in the nicardipine group than in the placebo group. In the control group, a placebo effect was observed with the ambulatory diastolic blood pressure recording, whereas it was not observed with hospital blood pressure measurements, especially when using the serial measurements performed for 30 min by an automatic recorder. The fall in blood pressure measured with the Remler recorder was correlated with the fall measured 10-20 min during one acute intravenous nicardipine perfusion before the trial, although the correlation coefficients do not suggest clinically relevant predictability of nicardipine efficacy at the individual level. The present findings support the need for controlled double-blind trials with careful office blood pressure measurements.

Acute hemodynamic effects of intravenous nicardipine in patients treated chronically with propranolol for coronary artery disease.

Intravenous nicardipine, 5 mg, was infused over 5 minutes in 2 comparable groups of 8 patients with chronic coronary artery disease but no clinical signs of heart failure. Eight patients had received no previous treatment and served as a control group; 8 other patients had received long-term treatment with large doses of propranolol. The hemodynamic responses to nifedipine were similar in the 2 groups, but was greater in patients taking propranolol. At 10 minutes, systemic vascular resistance decreased by 47% in patients taking propranolol and by 39% in the control group; mean aortic pressures decreased by 25% and 10%; heart rate increased by 23% and 19%; and cardiac index increased by 45% in both groups. At 20 minutes, left ventricular end-systolic volume index decreased by 20% in patients taking propranolol and 15% in the control patients; angiographic stroke index increased by 19% and 8%; left ventricular ejection fraction increased by 22% and 11%; and mean circumferential fiber velocity increased by 46% and 32%. Intravenous nicardipine infusion (5 mg) did not induce negative inotropic effects in patients with chronic coronary heart disease, and no evidence of congestive heart failure was seen, even in patients receiving large doses of propranolol. Nicardipine counteracted the potential deleterious effects of propranolol; increased peripheral vascular resistance and left ventricular stroke work and decreased cardiac output.

Capillary gas chromatographic determination with nitrogen-phosphorus detection of the calcium antagonist nicardipine and its pyridine metabolite M-5 in plasma.

A capillary gas chromatographic method with nitrogen-phosphorus detection for the simultaneous determination of nicardipine and its pyridine metabolite M-5 was developed. The method involves extraction of the plasma with hexane-methylene chloride (1:1, v/v), followed by evaporation of the organic phase. The extract is injected into a fused-silica capillary column coated with cross-linked 5% phenyl-methylsilicone. A temperature gradient (85-285 degrees C) is applied and the two products and the internal standard can be separated within 22 min. The limit of detection is 0.5 ng/ml for both products. The method is suitable for pharmacokinetic studies in humans.

Application of a system analysis approach to population pharmacokinetics and pharmacodynamics of nicardipine hydrochloride in healthy males.

Nicardipine hydrochloride, a dihydropyridine calcium channel blocker, possesses antihypertensive and arterial vasodilator properties. A system analysis approach, which makes fewer structural assumptions than compartmental methods, is presented for determining the pharmacokinetics and pharmacodynamics of nicardipine hydrochloride in healthy males following a discontinuous infusion at four dose levels. The results indicate that the average total body clearance of nicardipine is 0.920 L/h/kg and the volume of distribution is 0.275 L/kg. Nicardipine hydrochloride has a mean residence time in the body of 1.27 h, of which 0.324 h were spent in the systemic circulation and the remainder in the periphery. The determined pharmacokinetic model was linked to a pharmacodynamic model that allowed the change in the mean arterial blood pressure and heart rate to be described and predicted. A population pharmacokinetic-pharmacodynamic model was derived and the predictive power of the proposed model was assessed with a cross-validation technique that employs a relative predictive quotient for comparing the predictions to the fitted model. The results indicate that the proposed model describes the pharmacodynamics of nicardipine in healthy males and has good predictive ability when tested with a cross-validation procedure.

Influence of limonene on the bioavailability of nicardipine hydrochloride from membrane-moderated transdermal therapeutic systems in human volunteers.

The aim of the present study was to develop a membrane-moderated transdermal therapeutic system (TTS) of nicardipine hydrochloride using 2%w/w hydroxy propyl cellulose (HPC) gel as a reservoir system containing 4%w/w of limonene as a penetration enhancer. The permeability flux of nicardipine hydrochloride through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate (VA) content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED) on the permeability of nicardipine hydrochloride through EVA membrane 2825 (28% w/w VA) or membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE 4A MED/skin composite was higher than that coated with MA-31or MA-38. Thus a new TTS for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED and 2%w/w HPC gel as reservoir containing 4%w/w of limonene as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady state plasma concentration of the drug with minimal fluctuations for 20 h with improved bioavailability in comparison with the immediate release capsule dosage form.

High-performance liquid chromatographic determination of nifedipine, nicardipine and pindolol using a carbon fibre flow-through amperometric detector.

The electrochemical properties of the calcium-channel blockers, nifedipine and nicardipine, and the beta-blocking agent, pindolol, have been exploited for the determination of their concentrations in plasma samples. High-performance liquid chromatography (HPLC) separation was carried out on a cyanopropyl modified column and the drugs were detected in a flow-through carbon fibre microelectrode cell. The chromatographic system was coupled to a column-switching arrangement in order to perform on-line solid-phase extraction of the drugs from spiked human plasma. Preliminary investigations showed the response of the method to be linear over a range of 20-500 ng ml-1 in plasma with a limit of detection of approximately 15 ng ml-1 for each compound.

Adsorptive stripping voltammetry of nicardipine at a HMDE; determination of trace levels nicardipine in blood and urine.

The redox behaviour of nicardipine, a 1,4-dihydropyridine calcium antagonist, has been studied in different media on mercury, glassy carbon, gold and platinum electrodes using various voltammetric techniques. A highly sensitive adsorptive stripping voltammetric method for the determination of nicardipine based on adsorption of the drug onto mercury, followed by differential pulse voltammetric determination of the surface species, is described. All factors (pH, supporting electrolyte, accumulation potential and time, etc.) influencing adsorption as well as voltammetric response are discussed. The application of adsorptive stripping voltammetry at the hanging mercury drop electrode (HMDE) to the determination of trace levels of nicardipine in human urine and blood is illustrated, without an extraction procedure being necessary prior to the voltammetric measurement. A limit of detection of 4.8 ng per ml urine and 34 ng per ml blood is found with a mean recovery of nicardipine in urine and blood of 97%. The mean relative error does not exceed 6.5%.

Detection of the calcium antagonist nicardipine and its metabolites by gas chromatography-mass spectrometry.

An 89-year-old male patient, hospitalized with Parkinson's syndrome, suddenly died shortly after an intravenous drug injection. The conditions indicated that an overdose of nicardipine (1.3 mg/(mlkg)) may be given to the patient. At the autopsy, no pathological changes were noted. With a capillary gas chromatograph with mass spectrometer (GC-MS), nicardipine (4.97 microg/ml) and its pyridine metabolite (M-5, 5.0 microg/ml) were detected in the heart blood of the deceased. This result indicated that an overdose of intravenous nicardipine caused a sudden death of a patient in a poor condition.

The distribution of intravenous nicardipine in rat brain after subarachnoid hemorrhage.

The distribution of intravenously injected nicardipine in rat brain was investigated, as well as the influence of subarachnoid hemorrhage on its distribution. Autoradiographic studies demonstrated the accumulation of 3H-nicardipine only in the ventricles and subarachnoid spaces around pial vessels in normal brains. Thirty minutes after subarachnoid hemorrhage, the concentration of 3H-nicardipine was higher in the ventricles and in the subarachnoid space than that found in normal brains. It is concluded that nicardipine penetrates into the subarachnoid spaces and ventricles from pial vessels and/or choroid plexus, and that subarachnoid hemorrhage increases the penetration of nicardipine from vessels into the subarachnoid space.