Pharmacokinetic, bioequivalence, and safety assessments of two brands of 30-mg nifedipine controlled-release formulations in Chinese healthy subjects.

OBJECTIVE: This study aimed to analyze the pharmacokinetic (PK) characteristics, safety, and bioequivalence (BE) of a test (T) preparation of a nifedipine controlled-release tablet and the reference (R) drug (Adalat GTIS) in Chinese study participants in the context of fasting and postprandial states. MATERIALS AND METHODS: An open-label, single-center, randomized, single-dose, two-period study was designed including two separate arms, one with administration under fasting conditions and one with administration under postprandial conditions (high-fat, high-calorie breakfast). After oral administration, the nifedipine concentrations in plasma were quantitatively analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) at regular intervals. Primary PK parameters, including the area under the concentration curve from 0 to infinity (AUC0-∞), the area under the concentration profile from 0 to the last measurable concentration time (AUC0-t), and maximal measured plasma concentration (Cmax) were log-transformed with BE limits of 80 - 125% to evaluate BE. All adverse events (AEs) were wholly supervised. RESULTS: The PK profiles of the T and R formulations were comparable to each other under both fasting and postprandial conditions. The 90% confidence intervals (CIs) of the AUC0-∞, AUC0-t, and Cmax were 92.69 - 106.06%, 93.32 - 107.05%, and 99.53 - 116.71%, respectively, under the fasting state. The 90% CIs of the AUC0-∞, AUC0-t, and Cmax were 105.05 - 117.40%, 105.43 - 117.82%, and 102.66 - 116.30%, respectively, in the postprandial arm. 47 cases of drug-associated AEs were noted in the entire research. CONCLUSION: Under both the fasting and postprandial states, the two nifedipine controlled-release formulations were bioequivalent and safe in healthy Chinese subjects.

Formulation, Optimization, and In vivo Evaluation of Gastroretentive Drug Delivery System of Nifedipine for the Treatment of Preeclampsia.

The study aimed to develop gastroretentive drug delivery system of nifedipine, its optimization, and in vivo evaluation. Bilayered tablet of nifedipine was prepared using central composite design with 3 factors, 5 responses, and 15 experimental trials. Response surface methodology along with numerical and graphical optimization was used to select the best formulation. Scanning electron microscopy study of optimized tablet at different time interval was carried out which showed formation of porous structure on the tablet surface. In vivo studies for optimized formulation were carried out on 10 healthy human volunteers and obtained pharmacokinetic parameters were compared with the marketed formulation, "Nicardia XL." Optimized formulation containing 3.083 mg HPMC K15M, 29.859 mg HPMC E15LV, and 3.541 mg Carbopol 974P releases the drug in a desired manner and remain buoyant for more than 12 h in human stomach. Both the formulations were found to have similar in vitro release profile (f1 4.5089 and f2 55.8274) and also were found to be bioequivalent. Finally, the stability study of the optimized formulation proved the integrity of the optimized formulation. Hence, the data suggest gastroretention as a promising approach to enhance bioavailability of nifedipine.

Pharmacokinetic-pharmacodynamic analyses of antihypertensive drugs, nifedipine and propranolol, in spontaneously hypertensive rats to investigate characteristics of effect and side effects.

To investigate the relationship between the pharmacokinetics (PK) and effects and/or side-effects of nifedipine and propranolol, simultaneous examination of their PK and pharmacodynamics (PD), namely blood pressure (BP), heart rate (HR), and QT interval (QT), were assessed in spontaneously hypertensive rats as a disease model. Drugs were infused intravenously for 30 min, then plasma PK and hemodynamic effects were monitored. After general two-compartmental analysis was applied to the plasma data, PD parameters were calculated by fitting the data to PK-PD models. After nifedipine administration, the maximal hypotensive effect appeared about 10 min after starting the infusion, then BP started to elevate although the plasma concentration increased, supposedly because of a negative feedback mechanism generated from the homeostatic mechanism. After propranolol administration, HR decreased by half, and this bradycardic effect was greater than that with nifedipine. Wide variation in QT was observed when the propranolol concentration exceeded 700 ng/mL. This variation may have been caused by arrhythmia. Prolongation of QT with propranolol was greater than that with nifedipine, and bradycardia was slower than the concentration increase and QT prolongation. The characteristically designed PK-PD model incorporating a negative feedback system could be adequately and simultaneously fitted to both observed effect and side-effects.

Species differences and substrate specificity of CYP3A heteroactivation by efavirenz.

1. The purpose of this study was to clarify species differences in the heteroactivation of CYP3A substrates by efavirenz, which is known from clinical studies to activate midazolam 1'-hydroxylation, and to assess the feasibility of an animal model. 2. In monkey and human liver microsomes, efavirenz activated CYP3A-mediated midazolam 1'-hydroxylation, but had no effect in rat liver microsomes. The activating effect of efavirenz was also observed with recombinant human CYP3A4 and CYP3A5. Midazolam 4-hydroxylation, testosterone 6ß-hydroxylation and the oxidation of nifedipine were not activated by efavirenz in any of the microsomes. 3. In an in vivo study using monkeys, the AUC ratio of midazolam/1'-hydroxymidazolam was reduced from 0.85 to 0.30 by efavirenz treatment, which was comparable to that obtained in clinical studies. However, the AUC changes of midazolam caused by efavirenz were smaller than those observed in clinical results, therefore the effect of efavirenz on monkeys was not completely consistent with that seen in humans. 4. In conclusion, this is the first report that efavirenz specifically activates midazolam 1'-hydroxylation only in monkey and human liver microsomes, revealing marked species differences and high substrate specificity in the heteroactivation. A further study is required to clarify whether this in vitro result reflects the in vivo situation.

Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

OBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.

Desirability function approach for the optimization of an in-syringe ultrasound-assisted emulsification-microextraction method for the simultaneous determination of amlodipine and nifedipine in plasma samples.

In the present study, an in-syringe ultrasound-assisted emulsification-microextraction using a low-density organic solvent was developed for simultaneous extraction and pre-concentration of amlodipine besylate and nifedipine from plasma samples. The extracts were analyzed by high-performance liquid chromatography with UV detection. Central composite design combined with desirability function was applied to find out the optimal experimental conditions providing the highest global extraction efficiency. The optimal conditions identified were volume of the extracting solvent 45 µL, ionic strength 18.95% w/v, sonication time 2.58 min, and centrifugation time 3 min. Under the optimal conditions, the proposed method was evaluated, and applied to the analysis of amlodipine besylate and nifedipine in plasma samples. The validation results of the method indicated a wide linear range (2-1200 ng/mL) with a good linearity (r(2) >0.9991) and low detection limits (0.17 ng/mL for amlodipine besylate and 0.15 ng/mL for nifedipine) with RSD less than 5.2% for both components, both in intra- and inter-day precision studies. The applicability of the proposed in-syringe ultrasound-assisted emulsification-microextraction coupled to high-performance liquid chromatography with UV detection method was demonstrated by analyzing the drugs in spiked plasma samples.

Determination of nifedipine in dog plasma by high-performance liquid chromatography with tandem mass spectrometric detection.

Nifedipine is a dihydropyridine calcium channel blocker used widely in the management of hypertension and other cardiovascular disorders. In this work, a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry method was developed and validated to determine nifedipine in dog plasma using nimodipine as the internal standard. Chromatographic separation was carried out on a C8 column. The mobile phase consisted of a mixture of acetonitrile, water and formic acid (60:40:0.2, v/v/v) at a flow rate of 0.5 mL/min. Detection was performed on a triple quadrupole tandem mass spectrometer in selected reaction monitoring mode via an atmospheric pressure chemical ionization source. The method has a lower limit of quantification of 0.20 ng/mL with consumption of plasma as low as 0.05 mL. The linear calibration curves were obtained in the concentration range of 0.20-50.0 ng/mL (r = 0.9948). The recoveries of the liquid extraction method were 74.5-84.1%. Intra-day and inter-day precisions were 4.1-8.8 and 6.7-7.4%, respectively. The quantification was not interfered with by other plasma components and the method was applied to determine nifedipine in plasma after a single oral administration of two controlled-release nifedipine tablets to beagle dogs.

Sensitive LC-MS/MS-ESI method for simultaneous determination of nifedipine and atenolol in human plasma and its application to a human pharmacokinetic study.

A rapid, simple, sensitive and selective LC-MS/MS method has been developed and validated for quantification of nifedipine (NF) and atenolol (AT) in human plasma (250 µL). The analytical procedure involves a one-step liquid-liquid extraction method using carbamazepine as an internal standard (IS). The chromatographic resolution was achieved on a Hypurity Advance C(18) column using an isocratic mobile phase consisting of 5 mm ammonium acetate-acetonitrile (15:85, v/v) at flow rate of 1.0 mL/min. The LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. The total run time of analysis was 2 min and elution of NF, AT and IS occurred at 0.79, 1.04 and 0.76 min, respectively. A detailed method validation was performed as per the FDA guidelines and the standard curves found to be linear in the range of 1.02-101 ng/mL for NF and 5.05-503 ng/mL for AT, with a coefficient of correlation of ≥ 0.99 for both the drugs. NF and AT were found to be stable in a battery of stability studies, viz. bench-top, auto-sampler and repeated freeze-thaw cycles. The validated assay method was successfully applied to a pharmacokinetic study in humans.

Pharmacokinetics and Bioequivalence of 2 Nifedipine Controlled-Release Tablets: A Randomized, Single-Dose, 2-Period Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

The aim of this study was to evaluate the bioequivalence of generic nifedipine controlled-release tablet compared to branded product under fasting and fed conditions. A randomized, single-dose, 2-period, crossover study with a 7-day washout period was performed in 84 healthy Chinese volunteers (fasting cohort, n = 42; fed cohort, n = 42). In each study period, volunteers were assigned to receive a single oral dose of the generic or reference product (30 mg). Blood samples were collected before dosing and up to 72 hours after administration. The plasma concentration of nifedipine was determined by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained using a noncompartmental model and log-transformed pharmacokinetic parameters (maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, AUC from time 0 to infinity) were used to evaluate bioequivalence. The results showed that the 90% confidence interval for the geometric mean ratio of pharmacokinetic parameters of the test and reference products ranged from 80.0% to 125.0% in both the fasting and fed cohorts, meeting the criteria for bioequivalence. No serious adverse events were reported throughout the study and no adverse events led to withdrawal from the study. Food effects were found in both the test and reference products, with mean maximum plasma concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity increased by 23.7%, 20.7%, and 20.5%, respectively, for the test product and 35.2%, 13.4%, and 14.7% for the reference product after a high-fat and high-calorie breakfast.

Highly sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometry method for the determination of nifedipine in human plasma and its application to a bioequivalence study.

An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed for the determination of nifedipine in human plasma using nifedipine-d6 as the internal standard (IS). The plasma samples were prepared by solid-phase extraction on Phenomenex Strata-X cartridges employing 200 µL human plasma. Chromatography was carried out on Waters Acquity UPLC BEH C18 (50 × 2.1 mm, 1.7 µm particle size) analytical column under isocratic conditions using a mobile phase consisting of 4.0 mm ammonium acetate-acetonitrile (15:85, v/v). The precursor → product ion transitions for nifedipine (m/z 347.2 → 315.2) and IS (m/z 353.1 → 318.1) were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring and positive-ion mode. The method was validated over a wide dynamic concentration range of 0.050-150 ng/mL. Matrix effect was assessed by post-column analyte infusion and the mean extraction recovery was 95.6% across four quality control levels. The method is rugged and rapid with a total run time of 1.2 min and was applied to a bioequivalence study of 20 mg nifedipine tablet formulation in 30 healthy Indian subjects under fasting condition. Assay reproducibility was confirmed by reanalysis of 116 incurred samples.

Effects of ingestion of grapefruit juice or grapefruit on the hypotensive effect and plasma concentrations of dihydropyridine calcium antagonists (amlodipine and nifedipine): a case study.

The purpose of this study was to examine the effects of ingestion of grapefruit juice or grapefruit on the hypotensive effect and plasma concentration of dihydropyridine calcium antagonists, i.e., amlodipine and nifedipine. A 50-year-old man with essential hypertension was studied. Grapefruit juice (500 ml) was taken together with the antihypertensive drug, while one grapefruit was taken before drug ingestion. Blood pressures were measured using a digital automatic blood pressure monitor over a certain period. A single ingestion of grapefruit juice had no effect on plasma amlodipine concentration, but rapidly increased plasma nifedipine concentration and decreased blood pressure, while the effect on blood pressure was short-lasting. Grapefruit had no effect on either drug. It should be of concern that ingestion of a relatively large volume of grapefruit juice causes rapid decrease in blood pressure when the subject is treated by nifedipine.

Microminipig: A suitable animal model to estimate oral absorption of sustained-release formulation in humans.

We investigated the gastrointestinal absorption characteristics of oral sustained-release formulations in microminipigs, dogs, and monkeys in order to clarify the similarities in absorption properties between these animals and humans. Time profiles of oral absorption of nifedipine and valproic acid were calculated from the plasma concentration-time profiles of the drugs by a deconvolution method. The curves for both drugs in microminipigs were close to or slightly higher than those in humans, whereas those in monkeys were lower. Furthermore, the plasma concentration-time profiles of the drugs were subjected to non-compartmental analysis. The fractions of a dose absorbed into the portal vein (FaFg) in microminipigs ranged from 50 to 100% of the human values, whereas those in monkeys were less than half the human values. In addition, the other absorption-related parameters for the sustained-release formulation in microminipigs, as well as monkeys, were comparable to those in humans. In conclusion, the oral absorption properties of microminipigs and humans were similar regarding the sustained-release formulations. Therefore, microminipig is a suitable animal model to estimate the oral absorption of sustained-release formulations in humans.

Regulation of magnesium sulfate combined with nifedipine and labetalol on disease-related molecules in serum and placenta in the treatment of preeclampsia.

OBJECTIVE: To explore the regulatory effect of magnesium sulfate combined with nifedipine and labetalol on disease-related molecules in serum and placenta in the treatment of preeclampsia. PATIENTS AND METHODS: Altogether 100 patients with preeclampsia admitted to the Children & Women's Healthcare of Laiwu City were selected. They were divided into control group and experimental group according to different treatment methods. Among them, 51 patients in the control group were treated with magnesium sulfate combined with nifedipine, and 49 patients in the experimental group were treated with labetalol on the basis of the treatment in the control group. The therapeutic effects of the two methods were compared. The levels of the following factors in the two groups were compared: kallikrein expression, pregnancy-associated plasma protein A (PAPP-A), pregnancy-specific ß1 glycoprotein (SPI), placental growth factor (PLGF), human placental prolactin (HPL), transforming growth factor ß1(TGF-ß1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin in serum and placenta tissues. RESULTS: After treatment, the blood pressure in the experimental group was lower than that in the control group (p<0.05). The expression of kallikrein in serum and placental tissue of the patients in the experimental group was higher than that of the patients in the control group (p<0.05); PAPP-A level was lower than that in the control group (p<0.05); TGF-ß1 level was higher than that in the control group (p<0.05); VCAM-1 and E-selectin were lower than those in the control group (p<0.05), and kallikrein and TGF-ß1 in serum and placenta in the non-occurrence group were higher than those in the occurrence group (p<0.05). The serum and placenta PAPP-A, VCAM-1, and E-selectin in the non-occurrence group were lower than those in the occurrence group (p<0.05). CONCLUSIONS: Magnesium sulfate combined with nifedipine and labetalol has good efficacy in the treatment of preeclampsia. They can promote the expression of endogenous kallikrein, reduce the level of pregnancy-related hypertension predictors, and weaken the infiltration ability of cytotrophoblasts.

Population pharmacokinetics with a very small sample size.

The objective of this study was to evaluate whether pharmacokinetic parameters (clearance and volume of distribution of the central compartment) from a sparse sampling population pharmacokinetic study can be obtained with a very small sample size. For this study, three drugs were selected from the literature. The pharmacokinetics of all three drugs were studied in healthy adult subjects and plasma concentrations versus time data for individual subjects from extensive blood sampling were available. For population PK analysis, only five subjects were chosen and each subject gave either one or two blood samples. The estimated PK parameters from population PK analysis were compared with the PK parameters obtained from extensive sampling. The results of the study indicated that a reasonable estimate of PK parameters can be obtained with two blood samples from each subject with a sample size of five. The population PK study with sparse sampling scheme may be useful for PK studies in neonates and very young children and in subjects with rare diseases where sample size is small.

Development of nifedipine-loaded coated gelatin microcapsule as a long acting oral delivery.

To develop the long acting nifedipine oral delivery with enhanced bioavailability, nifedipine-loaded gelatin microcapsule containing nifedipine and ethanol in gelatin shell was prepared using a spray-dryer, and then coated microcapsule was prepared by coating the gelatin microcapsule with Eudragit acrylic resin. The dissolution test and the bioavailability of the coated microcapsule in rats were evaluated compared to nifedipine powder. The amount of nifedipine dissolved from gelatin microcapsule for 30 min increased about 5-fold compared to nifedipine powder in pH 1.2 simulated gastric fluid. Nifedipine released from the coated microcapsule was retarded in pH 1.2 simulated gastric fluid compared with that from gelatin microcapsule. Furthermore, the coated gelatin microcapsule maintained the plasma level of nifedipine over 4 h and gave significantly higher AUC of nifedipine than nifedipine powder. Thus, the Eudragit-coated gelatin microcapsule, which could maintain the plasma level of nifedipine over a longer period without the initial burst-out plasma concentration, is a preferable delivery system for poorly water-soluble nifedipine.

Pharmacokinetics of anorectal nifedipine and lidocaine (lignocaine) ointment following haemorrhoidectomy: an open-label, single-dose, phase IV clinical study.

OBJECTIVES: This study aimed to assess whether topical anorectal application of an ointment containing nifedipine (0.3% w/w) and lidocaine (lignocaine) [1.5% w/w] to patients undergoing Milligan-Morgan haemorrhoidectomy achieves pharmacologically relevant serum concentrations of the active ingredients and has any haemodynamic effects or adverse effects. METHODS: A single dose of 3 g of study ointment was circumferentially applied inside the anus to 24 patients (17 males and 7 females) aged 23-71 years (mean +/- SD: 42.9 +/- 4.9 years) during postoperative dressing after Milligan-Morgan haemorrhoidectomy from March 2007 to January 2008. Blood samples for the determination of nifedipine and lidocaine serum concentrations were drawn before surgery and at 20, 40, 60, 90, 120, 240, 360, 480 and 720 minutes after application. Serum concentrations of nifedipine and lidocaine were determined by a high-performance liquid chromatography method in order to calculate pharmacokinetic parameters. Patients' BP, heart rate and ECG readings were monitored during the study. RESULTS: Chromatographic signals of nifedipine were sporadically observed in only five patients (20.8%), consistent with therapeutically negligible concentrations and insufficient to permit calculation of any pharmacokinetic parameters. The serum concentrations of nifedipine in these five patients ranged from 5.9 to 18.8 ng/mL. Lidocaine concentrations were detectable in all patients. The means +/- SD and medians of pharmacokinetic parameters for lidocaine were as follows: maximum serum concentration (C(max)) 245.1 +/- 370.8 ng/mL, 73.6 ng/mL; time to reach C(max) (t(max)) 69.2 +/- 78.3 minutes, 40 minutes; area under the serum concentration-time curve from 0 to 6 hours (AUC(6)) 756.5 +/- 1254.1 ng.h/mL, 238.2 ng.h/mL. Only three patients had maximum serum concentrations above 1000 ng/mL (1037.8, 1044.75 and 1364.1 ng/mL). These outlier concentrations were four to five times lower than the threshold of CNS lidocaine toxicity (5000-6000 ng/mL). No serious local or systemic adverse events were observed throughout the study, and no subjects developed arrhythmias or significant ECG changes. Neither BP nor mean heart rate varied significantly after application of a single dose. CONCLUSIONS: This study demonstrates that single-dose topical application of an ointment containing nifedipine (0.3% w/w) and lidocaine (1.5% w/w) to patients undergoing Milligan-Morgan haemorrhoidectomy is safe to use. Following application onto damaged anorectal mucosa, nifedipine and lidocaine are absorbed into the bloodstream in small quantities that do not have any major implications for the safety of the product. Further studies are required to evaluate nifedipine and lidocaine concentrations in serum using a multiple-dose regimen.

Nifedipine concentration in maternal and umbilical cord blood after nifedipine gastrointestinal therapeutic system for tocolysis.

OBJECTIVE: To determine nifedipine concentrations in maternal plasma at steady state, and maternal and umbilical cord plasma at delivery, after tocolysis with nifedipine gastrointestinal therapeutic system (GITS) tablets. DESIGN: Prospective clinical pharmacokinetic study. SETTING: Department of Obstetrics at the Zurich University Hospital. POPULATION: Pregnant women treated for threatened preterm labour. METHODS: GITS dosage titrated to clinical response (30-150 mg/day). Nifedipine concentrations by high-performance liquid chromatography and turbo ion spray tandem mass spectrometry. MAIN OUTCOME MEASURES: Steady-state nifedipine concentrations in maternal blood and nifedipine concentrations in maternal and corresponding umbilical cord blood at delivery. RESULTS: Steady-state nifedipine concentrations (micrograms/l, mean +/- SE) were 54 +/- 6 (all doses, n = 31), 38 +/- 8 (60 mg/day, n = 13), and 92 +/- 12 (150 mg/day, n = 7) (P < 0.002). Umbilical cord and maternal concentrations both declined in a ln-linear regression with elimination half-lives of 20.4 and 17.4 hours. Linear regression showed a correlation between umbilical and maternal concentrations of 0.77 +/- 0.1 (n = 21, mean +/- SE). CONCLUSIONS: Steady-state plasma nifedipine concentrations after repeated dosing with nifedipine GITS 30-150 mg/day in pregnant women with preterm labour do not exceed 100 micrograms/l; fetal levels are 77% of maternal levels.

Pharmacokinetics of the analogs at C3 and C5 of m-nifedipine in beagle dogs.

The prototype 1,4-dihydropyridine (1,4-DHP) nifedipine, indicated for the management of hypertension and angina pectoris, has disadvantages including photodegradation and a short half-life. Several newer 1,4-DHPs, including m-nifedipine and its analogs at the C3, C5 position such as MN9201, MN9202 and MN9203, have been designed to offset these problems. The aim of this study was to investigate the pharmacokinetic characteristics of these derivatives to provide reference for their further evaluation and modification. Derivatives were intravenously bolus administered to beagle dogs. The drug concentration in the plasma was determined by the HPLC method. The pharmacokinetic parameters were calculated by the non-compartmental method. The analysis of variance (ANOVA) was used to compare the pharmacokinetic parameters of the derivatives. The results showed that the area under the curve from time zero to the last sampling time (AUC(0-t)) of m-nifedipine, MN9201, MN9202 and MN9203 was 45.1 +/- 13.6, 51.7 +/- 15.2, 70 +/- 16 and 62 +/- 12.4 micromol/l*min, respectively. The elimination half-life (t(1/2)) was 98 +/- 24, 129 +/- 55, 190 +/- 21 and 92 +/- 25 min, respectively. The t(1/2) of MN9202 was significantly longer than those of the others (p<0.05 or p<0.01). These results suggest that the length of the carbon chain at the C3 or C5 position in the derivatives had a marked effect on its metabolism, and M9202 is a promising new drug candidate worth further evaluation.

Effect of Lactobacillus casei on the absorption of nifedipine from rat small intestine.

Lactobacillus casei Shirota strain (L. casei) has a modulating effect on the production of cytokines, which often play important roles in drug metabolism, in the inflamed intestinal mucosa. We evaluated the effect of L. casei administered orally in advance for 4 weeks on the absorption of nifedipine from the rat small intestine. The maximum concentration of nifedipine in plasma after administration into the intestinal loop (0.8 mg/kg) was significantly higher in L. casei-treated rats (3.26 microg/mL) than in those untreated rats (2.33 microg/mL) by 40%. Accordingly, the bioavailability of nifedipine was tended to be higher in the former, while the effect of L. casei on the disposition of intravenously administered nifedipine was negligible. We also found that the availability of nifedipine for the passage through the intestinal mucosa was significantly increased in L. casei-treated rats from the single-pass intestinal perfusion experiments. Therefore, it is likely that the exposure to nifedipine after its administration into rat intestine was increased by oral ingestion of L. casei due to an increase in absorption by increased intestinal availability (decreased metabolic extraction) during passage through the intestinal mucosa. This study has suggested that L. casei has some effect on the metabolic activity in the intestinal mucosa, though it seems to be only mild.

Rapid and simultaneous determination of nifedipine and dehydronifedipine in human plasma by liquid chromatography-tandem mass spectrometry: Application to a clinical herb-drug interaction study.

Nifedipine (NIF), a calcium channel antagonist, is metabolized primarily by cytochrome P450 (CYP3A4) to dehydronifedipine (DNIF). As such, NIF is often used as a probe drug for determining CYP3A4 activity in human studies. A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated to simultaneously determine NIF and DNIF in human plasma using nitrendipine as the internal standard (IS). After extraction of the plasma samples by ether-n-hexane (3:1, v/v), NIF, DNIF and the IS were subjected to LC/MS/MS analysis using electro-spray ionization (ESI). Chromatographic separation was performed on a Hypersil BDS C(18) column (50 mm x 2.1 mm, i.d., 3 microm). The method had a chromatographic running time of approximately 2.5 min and linear calibration curves over the concentrations of 0.5-100 ng/mL for NIF and DNIF. The recoveries of the one-step liquid extraction method were 81.3-89.1% for NIF and 71.6-80.4% for DNIF. The lower limit of quantification (LLOQ) of the analytical method was 0.5 ng/mL for both analytes. The intra- and inter-day precision was less than 15% for all quality control samples at concentrations of 2, 10, and 50 ng/mL. The validated LC/MS/MS method has been successfully used to study pharmacokinetic interactions of NIF with the herbal antidepressant St. John's wort in healthy volunteers. These results indicated that the developed LC/MS/MS method was efficient with a significantly shorter running time (2.5 min) for NIF and DNIF compared to those methods previously reported in the literature. The presented LC/MS/MS method had acceptable accuracy, precision and sensitivity and was used in a clinical pharmacokinetic interaction study of NIF with St. John's wort, a known herbal inducer of CYP3A4. St. John's wort was shown to induce NIF metabolism with increased plasma concentrations of DNIF.