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.

Placental transfer of intravenous nicardipine and disposition into breast milk during the control of hypertension in women with pre-eclampsia.

OBJECTIVE: To assess nicardipine safety for fetuses and neonates. METHODS: Nicardipine was measured in maternal plasma (MP), umbilical cord arterial (UaP) and venous (UvP) plasma and breast milk (BrM) of 18 women with severe preeclampsia. RESULTS: Nicardipine was infused for a mean 11.9 ± 10.5 days before and 4.6 ± 1.6 days after delivery. Nicardipine dose and MP concentration were linearly correlated, as were MP with UaP, UvP, and BrM concentrations. The BrM/MP ratio was 0.06 to 0.30. The mean relative infant dose was 0.082%. CONCLUSION: Nicardipine is safe for fetuses and neonates due to its low levels of placental transfer and disposition in BrM.

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.

Microdose clinical trial: quantitative determination of nicardipine and prediction of metabolites in human plasma.

SUMMARY: A sample treatment procedure and high-sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantitative determination of nicardipine in human plasma were developed for a microdose clinical trial with nicardipine, a non-radioisotope labeled drug. The calibration curve was linear in the range of 1-500 pg/mL using 1 mL of plasma. Analytical method validation for the clinical dose, for which the calibration curve was linear in the range of 0.2-100 ng/mL using 20 microL of plasma, was also conducted. Each method was successfully applied to making determinations in plasma using LC/MS/MS after administration of a microdose (100 microg) and clinical dose (20 mg) to each of six healthy volunteers. We tested new approaches in the search for metabolites in plasma after microdosing. In vitro metabolites of nicardipine were characterized using linear ion trap-fourier transform ion cyclotron resonance mass spectrometry (LIT-FTICRMS) and the nine metabolites predicted to be in plasma were analyzed using LC/MS/MS. There is a strong possibility that analysis of metabolites by LC/MS/MS may advance to utilization in microdose clinical trials with non-radioisotope labeled drugs.

Determination of nicardipine and amlodipine in human plasma using on-line solid-phase extraction with a monolithic weak cation-exchange column.

An on-line solid-phase extraction (SPE)-HPLC method was developed for simultaneous screening of nicardipine and amlodipine in human plasma. A short monolithic poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) [p(GMA-EDMA)]-based weak cation-exchange (WCX) column was prepared and employed as the selective extraction sorbent, which exhibited good permeability and biocompatibility. During the on-line SPE protocol, high-abundance proteins (human serum albumin, immunoglobulin G, immunoglobulin A and transferrin) and most matrixes in plasma were fast removed while nicardipine and amlodipine were effectively trapped on this monolithic column. Furthermore, the monolithic WCX sorbent could be continuously reused more than 300 times without obvious changes in analytes extraction and proteins cleanup. The proposed method was linear over a range of 0.5-50.0 ng mL(-1) for both analytes with a linear regression coefficient greater than 0.998, and the limit of detection (LOD) for each analyte was 0.2 ng mL(-1). Validation assays also demonstrated acceptable precision and adequate recovery for simultaneous quantitative screening of nicardipine and amlodipine in human plasma. Real plasma samples from hypertensive patients receiving a dosing of 5mg antagonists were examined by using the proposed method. Results indicated that the on-line SPE-HPLC method could be applied for simultaneously monitoring of nicardipine and amlodipine in clinical plasma samples.

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.

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.

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.

[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.

Bioequivalence study of nicardipine solution versus nicardipine tablets.

The bioequivalence of a solution (investigational product) and a tablet (reference product) formulation of the dihydropyridine-type derivative Ca2+ antagonist nicardipine were investigated by measuring plasma levels of the compound after single randomized administration of 20 mg of the two formulations. Drugs were given orally in a single dose to 24 healthy volunteers (12 males and 12 females) at the beginning of the experiment and after a two weeks wash-out. Nicardipine is available in oral and intravenous formulations, the second being used for the short-term treatment of hypertensive crises. Oral formulations of nicardipine most diffused include immediate release (20 or 30 mg, three times a day administration), sustained release (30 mg, 45 mg or 60 mg, twice a day administration) and modified release (80 mg, once a day administration) tablets. A nicardipine solution is available only in Spain, but no published studies on the kinetics of this formulation are available. In the last 15 years, the main efforts were aimed to develop sustained or controlled release formulations of nicardipine to improve patient compliance by reducing the number of doses required each day. However, the use of twice a day or once a day administration of Ca2+ antagonists should be not overemphasized in particular situations like those of possible risk of cerebrovascular and/or coronary steal effect primarily in the elderly. The oral formulation of nicardipine investigated with a bioequivalence range > 70% compared to nicardipine immediate release tablets may represent an additional resource for treating elderly patients with concomitant cerebrovascular or coronary heart disease.

Formulation and in vivo evaluation of membrane-moderated transdermal therapeutic systems of nicardipine hydrochloride using carvone as a penetration enhancer.

A membrane-moderated transdermal therapeutic system (TTS) of nicardipine hydrochloride was developed using 2%w/w hydroxy propyl cellulose (HPC) gel as a reservoir system containing 8%w/w of carvone 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 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 2825 membrane (28%w/w vinyl acetate) or EVA 2825 membrane/skin composite also was studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new TTS for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED and 2%w/w HPC gel as reservoir containing 8%w/w of carvone 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 23 hr with improved bioavailability in comparison with the immediate-release capsule dosage form.

A simple method for nicardipine hydrochloride quantification in plasma using solid-phase extraction and reversed-phase high-performance liquid chromatography.

A simple and sensitive reversed-phase liquid chromatography method was developed and validated for the determination of nicardipine hydrochloride (NC) in rabbit plasma. Nicardipine hydrochloride and nimodipine, used as internal standard, were initially extracted from plasma by a rapid solid-phase extraction using C(18) cartridges. After extraction, nicardipine hydrochloride was separated by HPLC on a C(18) column and quantified by ultraviolet detection at 254 nm. A mixture of acetonitrile-0.02 M sodium phosphate buffer-methanol (45:40:15) with 0.2% of triethylamine of pH of 6.1 was used as mobile phase. The mean (+/-SD) extraction efficiency of NC was 77.56 +/- 5.4, 84.23 +/- 4.32 and 83.94 +/- 3.87% for drug concentrations of 5, 25 and 100 ng/mL, respectively. The method proved to be linear in the range of 5-100 ng/mL with a regression coefficient of 0.9993. The relative standard deviations of intra- and inter-day analysis for NC in plasma were 3.26-6.52% (n = 5) and 4.71-9.38% (n = 5), respectively. The differences of the mean value measured from the concentration prepared, expressed in percentages (bias percentage), were only - 5.2, 0.4 and 0.8% at NC 5, 25 and 50 ng/mL, which confirmed the accuracy of the method. The analytical technique was used to determine NC plasma concentration after drug oral administration to rabbits. The results inferred that NC is rapidly absorbed in rabbits and has a short half-life (t(1/2) = 1.34 h).

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.

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.

Effects of grapefruit juice on the stereoselective disposition of nicardipine in humans: evidence for dominant presystemic elimination at the gut site.

OBJECTIVES: To assess relative roles of the intestinal and hepatic stereoselective metabolism of nicardipine in an oral first-pass disposal with and without grapefruit juice intake. METHODS: The kinetic profiles of (+)- and (-)-nicardipine were studied in the six normal healthy male volunteers who received oral (40 mg) and intravenous (2 mg) racemic nicardipine, first with water and second with grapefruit juice. Both the enantiomers were determined by the stereoselective high-performance liquid chromatographic method, and hemodynamic parameters (arterial blood pressure, heart rate, and electrocardiogram) were assessed when each blood sample was taken. RESULTS: Grapefruit juice compared with water intake caused a significant (P < 0.05) increase in the mean oral (+)- and (-)-nicardipine bioavailability (Fobs) (48.6+/-5.0% and 105.6+/-7.8%) and dose-absorbed (Fabs) available fraction unmetabolized at the gut (Fg) (48.2+/-5.6% and 110.9+/-8.8%, respectively) with no significant change in the hepatic first-pass effect. However, all of the mean kinetic parameters of both the enantiomers after the intravenous dosing of racemic nicardipine did not differ between the grapefruit juice- and water-intake trial phases. The mean percentage changes in oral AUC (43.1+/-3.4% in [+]-nicardipine and 90.9 6.4% in [-]-nicardipine, or Fobs) and Fabs Fg by grapefruit juice tended to be greater for (-)-nicardipine than for (+)-nicardipine and the mean oral (+)/(-)-nicardipine AUC ratio was significantly reduced by grapefruit juice (from 2.25+/-0.37 to 1.75+/-0.28) (P < 0.05). Except for heart rates, which were greater with grapefruit juice (P < 0.05) at 1 and 2 h after the oral dose of nicardipine, the mean hemodynamic variables did not differ between the two trial phases. CONCLUSION: We conclude that the gut is the major presystemic disposal site of racemic nicardipine in humans. Grapefruit juice appears to affect this metabolic disposal of (-)-nicardipine to a somewhat greater extent compared with that of (+)-nicardipine, with an early postdose transient tachycardia after the oral dosing of racemic nicardipine.

Nicardipine did not activate renin-angiotensin-aldosterone system during isoflurane or sevoflurane anesthesia.

PURPOSE: To investigate the changes of renin-angiotensin-aldosterone system by nicardipine administration during isoflurane or sevoflurane anesthesia. METHODS: Twenty patients aged 40 to 70 yr for elective neurosurgery were studied. Anesthesia was induced with thiopental, midazolam and fentanyl and was maintained with nitrous oxide in oxygen and isoflurane or sevoflurane. When blood pressure was constant, 0.017 mg x kg(-1) nicardipine was administered as a bolus. Blood pressure, heart rate, and plasma concentrations of nicardipine, angiotensin I and II, aldosterone and renin activity were measured for 30 min after nicardipine administration. RESULTS: Blood pressure decreased for 30 min after nicardipine administration in both groups with lower values during sevoflurane anesthesia. Heart rate increased only in the isoflurane group. Plasma nicardipine concentrations did not differ between isoflurane and sevoflurane groups. Plasma renin activity and concentrations of angiotensin II and aldosterone did not change in either groups and there were no differences between groups. Plasma concentration of angiotensin I increased at 20 and 30 min after nicardipine administration in the isoflurane group but not in the sevoflurane group. CONCLUSION: The activity of renin-angiotensin-aldosterone system did not increase by a single dose administration of nicardipine in isoflurane or sevoflurane anesthesia.

Evaluation of the effect of polyethylene glycol 400 on the nasal absorption of nicardipine and verapamil in the rat.

This study has investigated the effect of polyethylene glycol (PEG) 400 on the intranasal absorption and ensuing pharmacokinetics of the calcium entry blockers nicardipine and verapamil in a rat model. To solutions of nicardipine in acetate buffer pH 5.0 and of verapamil in distilled water, PEG 400 was added in concentrations of 0-5%. The nasal bioavailability of nicardipine from plain buffered solution was 44%, and increased steadily to 56-79% in direct proportion to the amount of PEG 400 added. Verapamil, on the other hand, exhibited an intranasal bioavailability of 52% in the absence of PEG 400, and between 61-68% in the presence of increasing concentrations of PEG 400. None of the formulations tested was found to cause adverse effects on the morphology and integrity of the nasal mucosa.

Extraction and quantification of nicardipine in human plasma.

A novel simple method of extraction, separation, identification and quantification of nicardipine in human plasma samples was completely studied. The human plasma samples were initially purified by solid-phase extraction (SPE) using a C18 cartridge. The extracted samples were separated and nicardipine present in the samples was quantified by high-performance liquid chromatography (HPLC) on a reversed-phase C18 column employing a mobile phase consisting of 60% (v/v) acetonitrile in 0.02 M NaH2PO4 with pH of 6.3 and a variable wavelength UV detector set at 254 nm. The recovery of nicardipine from plasma samples using selective SPE was 91+/-6.0% and had less interfering compounds in the HPLC analysis compared to the use of liquid-liquid (L/L) extraction. In the HPLC analysis, examining the effect of pH values of the mobile phase on the capacity factor (k') of nicardipine revealed a method for selecting a critical k' value of nicardipine to eliminate interfering peaks near the peak specific to the analyte. This method for quantification of nicardipine in human plasma samples was suitable for studying the pharmacokinetic profile of nicardipine administered as an intravenous bolus to cardiac surgical patients.

A high-performance liquid chromatographic method for the determination of nicardipine in plasma and its application to pharmacokinetics in humans.

A simple and sensitive reversed-phase liquid chromatographic method has been developed and validated for the analysis of nicardipine in human plasma and the study of the pharmacokinetics of the drug in human body. Nicardipine and nimodipine (internal standard) in plasma were extracted with hexane-butanol (12:1, v/v) after addition of borate buffer (0.5 mol/mL, pH = 9.0), and then measured by HPLC using a Hypersil C18 column as stationary phase and acetonitrile--KH2PO4 buffer (0.015 M, pH = 5.5)--triethylamine as mobile phase. Nicardipine was quantified by ultraviolet absorbance at 236 nm. The method proved to be linear in the clinical range of 5-200 ng/mL with a regression coefficient of 0.9998. The lower limit of detection of nicardipine in plasma was 2.5 ng/mL. Intra- and inter-day coefficients of variation of assay for nicardipine in plasma were 3.5-5.4% (n = 7) and 5.2-6.4% (n = 5), respectively. The recovery of nicardipine was 92.8-100.8% for plasma. The method has been used to determine nicardipine in plasma samples from 10 volunteers and provided data on the pharmacokinetics of the drug. The results inferred that nicardipine is absorbed rapidly and has a relatively short half-life in healthy individuals. The data obtained was fitted with a 3P87 program to study the pharmacokinetics. The results showed that the disposition of nicardipine was conformed to a two-compartment open model with Tmax = 1.6 +/- 0.3 h, Cmax = 109.8 +/- 38.7 ng/mL, T1/2 = 5.35 +/- 2.28 h and AUC0-->infinity = 322.1 +/- 69.6 ng/h/mI.