Plasma Nifedipine Concentration Research Articles

Fabrication, evaluation, and enhanced penetration of vinyl and cellulose-engineered transdermal patch of nifedipine using essential oil as penetration enhancer

The aim of this study was to develop and evaluate the transdermal patch formulations of nifedipine. The patch formulations containing nifedipine were prepared and optimized with different ratios of vinyl and cellulose-derived polymers, drug contents, and permeation enhancers. Among the various formulations, the patch formulation containing a 1:5 ratio of ethyl cellulose and polyvinyl pyrrolidone was selected for ex vivo pharmacokinetic study based on in vitro permeation studies using stratum corneum of the pig’s skin. The cumulative percentage release after the transdermal administration of the optimized patch formulation was 71.43%, and the plasma concentration of nifedipine was maintained for 16 hrs. The physicochemical evaluation study including flatness, thickness, moisture content and uptake, drug content in vitro release, and ex vivo permeation indicated satisfactory results. The formulation batch with clove oil as a penetration enhancer has shown better ex vivo permeation as compared to the formulations without enhancers and another synthetic enhancer. These results suggest that the optimized patch formulation Q3 could be further developed for clinical applications, providing the therapeutic plasma level of nifedipine over an extended period. Hence analyzing the results of the evaluation tests, in vitro and ex vivo data on the preparation and optimization of nifedipine-loaded transdermal patch, it can be concluded that the formulation shows its feasibility as an effective transdermal delivery system for nifedipine.

Comparative Bioequivalence and Food Effect of Two Formulations of 30-mg Nifedipine Controlled-Release Tablets in Healthy Chinese Adults.

Nifedipine is a potent antihypertensive medication classified as a dihydropyridine calcium channel blocker. The objective of this trial was to assess the bioequivalence of a 30-mg nifedipine controlled-release tablet and a reference drug in a cohort of healthy Chinese individuals. Two independent open-label, randomized, single-dose, crossover studies were conducted, 1 under fasting conditions (N = 44, with 1 participant dropping out midway) and the other under fed conditions (N = 44, with 4 participants dropping out midway). Plasma concentrations of nifedipine were determined using liquid chromatography-mass spectrometry, and pharmacokinetic (PK) parameters were calculated using noncompartmental analysis with Phoenix WinNonlin 8.0 software. In both fasting and fed studies, reasonable bioequivalence was observed for the PK parameters of both the test product and the reference drug. A good safety profile was demonstrated for both the test product and reference drug, with no serious adverse events reported, and both were similarly well tolerated. An important observation with food coadministration was that systemic exposure to nifedipine (based on area under the curve, AUC0-∞) was reduced by approximately 12%. The bioequivalence of the test product and reference drug under fasting/fed conditions in healthy subjects in China was demonstrated by the study results.

The Development and Validation of a Novel "Dual Cocktail" Probe for Cytochrome P450s and Transporter Functions to Evaluate Pharmacokinetic Drug-Drug and Herb-Drug Interactions.

This study was designed to develop and validate a 10 probe drug cocktail named “Dual Cocktail”, composed of caffeine (Cyp1a2 in rat and CYP1A2 in human, 1 mg/kg), diclofenac (Cyp2c11 in rat and CYP2C9 in human, 2 mg/kg), omeprazole (Cyp2c11 in rat and CYP2C19 in human, 2 mg/kg), dextromethorphan (Cyp2d2 in rat and CYP2D6 in human, 10 mg/kg), nifedipine (Cyp3a1 in rat and CYP3A4 in human, 0.5 mg/kg), metformin (Oct1/2 in rat and OCT1/2 in human, 0.5 mg/kg), furosemide (Oat1/3 in rat and OAT1/3 in human, 0.1 mg/kg), valsartan (Oatp2 in rat and OATP1B1/1B3 in human, 0.2 mg/kg), digoxin (P-gp in rat and human, 2 mg/kg), and methotrexate (Mrp2 in rat and MRP2 in human, 0.5 mg/kg), for the evaluation of pharmacokinetic drug–drug and herb-drug interactions through the modulation of a representative panel of CYP enzymes or transporters in rats. To ensure no interaction among the ten probe substrates, we developed a 2-step evaluation protocol. In the first step, the pharmacokinetic properties of five individual CYP probe substrates and five individual transporter substrates were compared with the pharmacokinetics of five CYP cocktail or five transporters cocktails in two groups of randomly assigned rats. Next, a pharmacokinetic comparison was conducted between the CYP or transporter cocktail group and the dual cocktail group, respectively. None of the ten comparison groups was found to be statistically significant, indicating the CYP and transporter substrate sets or dual cocktail set could be concomitantly administered in rats. The “Dual Cocktail” was further validated by assessing the metabolism of nifedipine and omeprazole, which was significantly reduced by a single oral dose of ketoconazole (10 mg/kg); however, no changes were observed in the pharmacokinetic parameters of other probe substrates. Additionally, multiple oral doses of rifampin (20 mg/kg) reduced the plasma concentrations of nifedipine and digoxin, although not any of the other substrates. In conclusion, the dual cocktail can be used to characterize potential pharmacokinetic drug–drug interactions by simultaneously monitoring the activity of multiple CYP isoforms and transporters.

Clinical Pharmacology Aspects of Some Tocolytic Drugs Used in Pregnant Women at Risk of Preterm Birth

Spontaneous preterm birth is one of the most pressing issues in obstetrics, as it remains one of the leading causes of newborn morbidity and mortality. Pending issues of aetiology, pathogenesis, and absence of medicinal products indicated for the treatment of spontaneous preterm labour pose a challenge for rational pharmacotherapy. The paper presents the results of a scientific literature review on the problem of rational pharmacotherapy of spontaneous preterm labour using tocolytic drugs — calcium channel blockers, cyclooxygenase inhibitors. The paper summarises specific pharmacokinetic parameters of these drugs during pregnancy. It discusses pharmacogenetic aspects of using tocolytic drugs in pregnant women and their potential clinical effects. It was demonstrated that women with threatened miscarriage had high interindividual variability in nifedipine plasma concentrations depending onCYP3A5genotype. It was shown that certain genetic polymorphisms ofCYP2C9may lead to an increased metabolic rate and an increase in indomethacin clearance resulting in the reduction of its efficacy. Yet, there is minimal research regarding this issue. Therefore, further research is needed to assess the impact ofCYP3A5andCYP2C9genotypes on the efficacy and safety of nifedipine and indomethacin used as tocolytic drugs in obstetrics.

ABCG2 c.421C>A polymorphism alters nifedipine transport to breast milk in hypertensive breastfeeding women

Nifedipine, a known substrate to breast cancer resistance protein (ABCG2/BCRP), is used for the treatment of hypertension during breastfeeding. This study aimed to evaluate the effect of ABCG2 c.421C>A on nifedipine transfer to breast milk (BM) in hypertensive women. Nineteen hypertensive breastfeeding women treated with 20 mg nifedipine every 12 hours were investigated. Blood and BM samples were collected simultaneously 15–30 days after delivery and at least 15 days after drug treatment. Patients genotyped as ABCG2 c.421CC showed nifedipine plasma and BM concentrations ranging from 8.32–178.1 ng/mL and 4.8–58.5 ng/mL, respectively. ABCG2 c.421C>A showed a trend towards significance (p = 0.0793) on nifedipine in BM, with concentrations approximately 3 times higher in the heterozygous 421 CA (29 ng/mL) in comparison to 421 CC (10.5 ng/mL). Nifedipine BM/plasma ratio was significantly lower in 421CC when compared to 421CA (p = 0.01). In conclusion, ABCG2 c.421C>A polymorphism is associated with higher transfer of nifedipine to BM.

Effect of type 2 diabetes mellitus on the pharmacokinetics and transplacental transfer of nifedipine in hypertensive pregnant women.

Diabetes mellitus can inhibit cytochrome P450 3A4, an enzyme responsible for the metabolism of nifedipine, used for the treatment of hypertension in pregnant women. We aimed to assess the effect of type 2 diabetes mellitus (T2DM) on the pharmacokinetics, placental transfer and distribution of nifedipine in amniotic fluid in hypertensive pregnant women. The study was conducted in 12 hypertensive pregnant women [control group (CG)] and 10 hypertensive pregnant women with T2DM taking slow-release nifedipine (20mg, 12/12h). On the 34th week of gestation, serial blood samples were collected (0-12h) after administration of the medication. At delivery, samples of maternal and fetal blood and amniotic fluid were collected for determination of nifedipine distribution in these compartments. The median pharmacokinetic parameters of CG were: peak plasma concentration (Cmax ) 26.41ngml-1 , time to reach Cmax (tmax ) 1.79h, area under the plasma concentration vs. time curve from 0-12h (AUC0-12 ) 235.99ng.hml-1 , half-life (t½) 4.34h, volume of distribution divided by bioavailability (Vd/F) 560.96l, and ClT /F 84.77lh-1 . The parameters for T2DM group were: Cmax 23.52ngml-1 , tmax 1.48h, AUC0-12 202.23ng.hml-1 , t½ 5.00h, Vd/F 609.40l, and apparent total clearance (ClT /F) 98.94lh-1 . The ratios of plasma concentrations of nifedipine in the umbilical vein, intervillous space and amniotic fluid to those in the maternal vein for CG and T2DM were 0.53 and 0.44, 0.78 and 0.87, respectively, with an amniotic fluid/maternal plasma ratio of 0.05 for both groups. The ratios of plasma concentrations in the umbilical artery to those in the umbilical vein were 0.82 for CG and 0.88 for T2DM. There was no influence of T2DM on the pharmacokinetics or placental transfer of nifedipine in hypertensive women with controlled diabetes.

74 Relationship between plasma concentration of nifedipine and pressure control in hypertensive pregnant women

Introduction Nifedipine is a calcium channel blocker used in treatment of hypertension in pregnant women. Objective The objective of the present study was to investigate the relation between the plasma concentration of nifedipine and pressure control in hypertensive pregnant women. Methods Twenty-two hypertensive pregnant women taking oral slow-release nifedipine 20 mg every 12 h were evaluated. Serial blood samples were collected at times 0–12 h after administration of the last nifedipine dose during the third trimester of pregnancy. The blood pressure of the patients was measured 4 in 4 hours from the time 0 to 12 h. Concentrations of nifedipine were determined by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The plasma concentration and the mean arterial pressure were reported as mean and standard deviation. Results The maximum fall in the measurement of mean arterial pressure after 4 h (95.4 ± 10.2 mmHg) was observed right after the mean maximum plasma concentration (27.5 ± 10.6 ng/mL) at time of maximum concentration (1.5 ± 0.5 h). As well as the values of mean arterial pressure at time 12 h (102.0 ± 11.1 mmHg) was similar to the values from time zero (106.8 ± 11.5 mmHg). Conclusion The study demonstrate the action of the drug during the dose interval used, as well as its efficacy. Acknowledgement Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq).

Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

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. 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. 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. 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. 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.

Effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats.

The purpose of this study was to investigate the possible effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The effects of pioglitazone on P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4 activities were also evaluated. Nifedipine was mainly metabolized by CYP3A4. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined after oral and intravenous administrations of nifedipine to rats in the presence and absence of pioglitazone (0.3 and 1.0mg/kg). Pioglitazone inhibited the CYP3A4 enzyme activity in a concentration-dependent manner. Inhibitory concentration (IC50) was 12.1μM. In addition, pioglitazone significantly increased the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The areas under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (C max) of nifedipine were significantly increased by 52.1 and 59.1%, respectively, in the presence of pioglitazone (1.0mg/kg) compared with control group. The total body clearance (CL/F) of nifedipine was significantly (1.0mg/kg) decreased by pioglitazone (35.8%). Consequently, the absolute bioavailability (AB) of nifedipine in the presence of pioglitazone (1.0mg/kg) was significantly higher (25.3%) than that of the control. The metabolite-parent AUC ratio (MR) in the presence of pioglitazone (1.0mg/kg) significantly decreased (23.9%) compared to that of the control group. The increased bioavailability of nifedipine in the presence of pioglitazone may be due to an inhibition of the P-gp-mediated efflux transporter in the small intestine and to the inhibition of the metabolism by inhibition of CYP3A4 in the small intestine and/or the liver, and/or to a reduction of CL/F of nifedipine by pioglitazone.

Human lymphatic vessel contractile activity is inhibited in vitro but not in vivo by the calcium channel blocker nifedipine.

Calcium channel blockers (CCB) are widely prescribed anti-hypertensive agents. The commonest side-effect, peripheral oedema, is attributed to a larger arterial than venous dilatation causing increased fluid filtration. Whether CCB treatment is detrimental to human lymphatic vessel function and thereby exacerbates oedema formation is unknown. We observed that spontaneous lymphatic contractions in isolated human vessels (thoracic duct and mesenteric lymphatics) maintained under isometric conditions were inhibited by therapeutic concentrations (nanomolar) of the CCB nifedipine while higher than therapeutic concentrations of verapamil (micromolar) were necessary to inhibit activity. Nifedipine also inhibited spontaneous action potentials measured by sharp microelectrodes. Furthermore, noradrenaline did not elicit normal increases in lymphatic vessel tone when maximal constriction was reduced to 29.4±4.9% of control in the presence of 20nmoll(-1) nifedipine. Transcripts for the L-type calcium channel gene CACNA1C were consistently detected from human thoracic duct samples examined and the CaV1.2 protein was localized by immunoreactivity to lymphatic smooth muscle cells. While human lymphatics ex vivo were highly sensitive to nifedipine, this was not apparent in vivo when nifedipine was compared to placebo in a randomized, double-blinded clinical trial: conversely, lymphatic vessel contraction frequency was increased and refill time was faster despite all subjects achieving target nifedipine plasma concentrations. We conclude that human lymphatic vessels are highly sensitive to nifedipine in vitro but that care must be taken when extrapolating in vitro observations of lymphatic vessel function to the clinical situation, as similar changes in lymphatic function were not evident in our clinical trial comparing nifedipine treatment to placebo.

Effects of licochalcone A on the bioavailability and pharmacokinetics of nifedipine in rats: possible role of intestinal CYP3A4 and P-gp inhibition by licochalcone A.

The purpose of this study was to investigate the possible effects of licochalcone A (a herbal medicine) on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The pharmacokinetic parameters of nifedipine and/or dehydronifedipine were determined after oral and intravenous administration of nifedipine to rats in the absence (control) and presence of licochalcone A (0.4, 2.0 and 10 mg/kg). The effect of licochalcone A on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was also evaluated. Nifedipine was mainly metabolized by CYP3A4. Licochalcone A inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC50 ) of 5.9 μm. In addition, licochalcone A significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The area under the plasma concentration-time curve from time 0 to infinity (AUC) and the peak plasma concentration (Cmax ) of oral nifedipine were significantly greater and higher, respectively, with licochalcone A. The metabolite (dehydronifedipine)-parent AUC ratio (MR) in the presence of licochalcone A was significantly smaller compared with the control group. The above data could be due to an inhibition of intestinal CYP3A4 and P-gp by licochalcone A. The AUCs of intravenous nifedipine were comparable without and with licochalcone A, suggesting that inhibition of hepatic CYP3A4 and P-gp was almost negligible.

Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: Possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors

BackgroundThis study aimed to investigate the effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats. MethodsWe determined the pharmacokinetic parameters of nifedipine and dehydronifedipine in rats after oral and intravenous administration of nifedipine without and with HMG-CoA reductase inhibitors.We evaluated the effect of HMG-CoA reductase inhibitors on the activity of P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4. ResultsAtorvastatin, fluvastatin, pravastatin and simvastatin inhibited CYP3A4 activities; inhibitory concentration (IC50) values were 47.0, 5.2, 15.0 and 3.3μM, respectively. Simvastatin and fluvastatin increased the cellular uptake of rhodamine-123.The area under the plasma concentration–time curve (AUC0–∞) and the peak plasma concentration (Cmax) of oral nifedipine were significantly increased by fluvastatin and simvastatin, respectively, compared to control group. The total body clearance (CL/F) of nifedipine after oral administration with fluvastatin and simvastatin were significantly decreased compared to those of control. The metabolite–parent AUC ratio (MR) of nifedipine with fluvastatin and simvastatin were significantly decreased, which suggested that fluvastatin and simvastatin inhibited metabolism of nifedipine, respectively. The AUC0–∞ of intravenouse nifedipine with fluvastatin and simvastatin was significantly higher than that of the control group. ConclusionThe increased bioavailability of nifedipine may be mainly due to inhibition of both P-gp in the small intestine and CYP3A subfamily-mediated metabolism of nifedipine in the small intestine and/or in the liver and to the reduction of the CL/F of nifedipine by fluvastatin and simvastatin.

Lipid nanoparticles with no surfactant improve oral absorption rate of poorly water-soluble drug

A pharmacokinetic study was performed in rats to evaluate the oral absorption ratios of nanoparticle suspensions containing the poorly water-soluble compound nifedipine (NI) and two different types of lipids, including hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol. NI-lipid nanoparticle (LN) suspensions with a mean particle size of 48.0 nm and a zeta potential of -57.2 mV were prepared by co-grinding combined with a high-pressure homogenization process. The oral administration of NI-LN suspensions to rats led to a significant increase in the NI plasma concentration, and the area under the curve (AUC) value was found to be 108 min μg mL⁻¹, indicating a 4-fold increase relative to the NI suspensions. A comparison of the pharmacokinetic parameters of the NI-LN suspensions with those of the NI solution prepared using only the surfactant polysorbate 80 revealed that although the AUC and bioavailability (59%) values were almost identical, a rapid absorption rate was still observed in the NI-LN suspensions. These results therefore indicated that lipid nanoparticles prepared using only two types of phospholipid with a mean particle size of less than 50 nm could improve the absorption of the poorly water-soluble drug.

A PBPK Model to Predict Disposition of CYP3A‐Metabolized Drugs in Pregnant Women: Verification and Discerning the Site of CYP3A Induction

Besides logistical and ethical concerns, evaluation of safety and efficacy of medications in pregnant women is complicated by marked changes in pharmacokinetics (PK) of drugs. For example, CYP3A activity is induced during the third trimester (T3). We explored whether a previously published physiologically based pharmacokinetic (PBPK) model could quantitatively predict PK profiles of CYP3A-metabolized drugs during T3, and discern the site of CYP3A induction (i.e., liver, intestine, or both). The model accounted for gestational age-dependent changes in maternal physiological function and hepatic CYP3A activity. For model verification, mean plasma area under the curve (AUC), peak plasma concentration (Cmax), and trough plasma concentration (Cmin) of midazolam (MDZ), nifedipine (NIF), and indinavir (IDV) were predicted and compared with published studies. The PBPK model successfully predicted MDZ, NIF, and IDV disposition during T3. A sensitivity analysis suggested that CYP3A induction in T3 is most likely hepatic and not intestinal. Our PBPK model is a useful tool to evaluate different dosing regimens during T3 for drugs cleared primarily via CYP3A metabolism.

Prospective, Open, Non-Randomized Study to Evaluate Influence of Hemodialysis on the Plasma Concentration of Nifedipine

Prospective, Open, Non-Randomized Study to Evaluate Influence of Hemodialysis on the Plasma Concentration of Nifedipine

Effect of nifedipine on anorectal sensorimotor functions in health and fecal incontinence

The mechanisms of increased rectal stiffness in women with fecal incontinence (FI) and rectal urgency are not understood. Our hypothesis was that distention-induced activation of mechanosensitive L-type calcium channels in smooth muscle contributes to increased rectal stiffness in FI. Anal pressures, rectal distensibility (compliance, capacity, and contractile response to sinusoidal oscillation), and rectal sensation were assessed before and after oral nifedipine (30 + 10 mg) or placebo in 16 women with FI and 16 asymptomatic women. At baseline, FI patients had a lower anal pressure increment during squeeze (health, 66.9 ± 7.6: FI, 28.6 ± 5.9, mean ± SE, P ≤ 0.01), lower rectal capacity (P = 0.052), and higher rectal pressures during sinusoidal oscillation (health, 13.7 ± 3.2: FI, 21.7 ± 1.4, mean ± SE, P = 0.02) than the healthy women, which suggests an exaggerated rectal contractile response to distention. Nifedipine decreased mean BP, increased heart rate (P = 0.01 vs. placebo), and reduced anal resting pressure (P ≤ 0.01) but did not significantly modify rectal distensibility in health or FI. Plasma nifedipine concentrations (health, 103 ± 21 ng/ml: FI, 162 ± 34 ng/ml) were correlated with increased rectal compliance (r = 0.6, P = 0.02) in all study participants and, in healthy subjects, with decreased rectal pressures during sinusoidal oscillation (r = 0.86, P = 0.01), indicative of reduced stiffness. No consistent effects on rectal perception were observed. These observations confirm that FI is associated with anal weakness and increased rectal stiffness. At therapeutic plasma concentrations, nifedipine reduced anal resting pressure but did not improve rectal distensibility in FI, outcomes that argue against a predominant contribution of myogenic L-type calcium channels to reduced rectal distensibility in FI.

Effect of Diallyl Trisulfide on the Pharmacokinetics of Nifedipine in Rats

This study aimed to evaluate the effect of diallyl trisulfide (DATS), a major component derived from garlic, on the pharmacokinetics of nifedipine. Pharmacokinetic parameters of nifedipine were determined in rats following an oral gavage (3 mg/kg) or intravenous administration (0.75 mg/kg) of nifedipine with co-administration of DATS (20 mg/kg) and long-term pretreatment of DATS (20 mg/kg/d for 15 consecutive days). Compared to the control groups, higher C(max) and AUC(0-24 h) were observed for oral gavage of nifedipine after short-term and long-term pretreatment of DATS, whereas those for intravenous nifedipine were little changed. The oral bioavailabilities of nifedipine were remarkably enhanced via the concomitant use of DATS. In conclusion, DATS increased the oral exposure of nifedipine in rats likely by the modification of intestinal metabolism of nifedipine, indicating that combined use of DATS or DATS-containing supplement with nifedipine may require caution because high plasma concentrations may lead to an undesired toxicity of this agent. Practical Application: Patients suffering from cardiovascular disease should take caution in combined use of DATS or DATS-rich garlic supplement with nifedipine because long-term treatment of DATS could lead high plasma concentrations of nifedipine.

Simultaneous delivery of Nifedipine and Metoprolol tartarate using sandwiched osmotic pump tablet system

The sandwiched osmotic tablet system that could deliver Nifedipine and Metoprolol tartarate simultaneously for extended period of time was developed in order to reduce the problems associated with multidrug therapy of hypertension. This system composed of a middle push layer and attached drug layers of Nifedipine and Metoprolol. The advantage of the sandwiched osmotic tablet system over the commercialized push–pull osmotic tablet system is its simplicity of preparation, as the surface identification was avoided. Polyethylene oxide 600,000 and 8,000,000 g/mole were used as thickening agent of drug layer and the expandable hydrogel of push layer, respectively. It has been observed that amount of polyethylene oxide (PEO) and KCL of the drug and push layer had profound influence on Nifedipine and Metoprolol release. Further, the release of drugs was optimized by the size of the delivery orifice, level of plasticizer and membrane thickness. The optimal osmotic pump tablet was found to deliver both drugs at a rate of approximately zero order for up to 16 h independent of pH and agitational intensity, but dependent on the osmotic pressure of the release media. The formulations were found to be stable after 3 months of accelerated stability studies. Prediction of steady-state levels showed the plasma concentrations of Nifedipine and Metoprolol to be within the desired range. Further sandwiched system had a good sustained effect in comparison with the conventional product. Hence the prototype design of the system could be applied to other combinations of drugs used for cardiovascular diseases, diabetes, etc.

Effect of food components and dosing times on the oral pharmacokinetics of nifedipine in rats

The present study was aimed to investigate the effect of food components and dosing time on the oral exposure of nifedipine in rats. Nifedipine was given orally to rats with and without food components at 8:00 a.m. (morning time) or 4:00 p.m. (evening time) during winter periods. Food components included milk, sodium chloride, oleic acid, and sodium taurocholate. Plasma concentration profiles of nifedipine showed double peak phenomena which were generally retained regardless of food components, vehicle types and the dosing time. Sodium chloride, milk and sodium taurocholate significantly increased the AUC while oleic acid did not, when drug was dosed in the morning time. After the dosing in the evening time, milk and sodium chloride significantly increased the plasma concentrations of nifedipine but oleic acid and sodium taurocholate decreased them. Overall, the systemic in vivo exposure of nifedipine was invariably lower with the evening dosing compared to the dosing in the morning, but this circadian rhythm dependency was not reversed by the multiple dosing of food components in rats. Food components and dosing time significantly altered the oral pharmacokinetics of nifedipine in rats, implying that the altered bioavailability and higher plasma concentrations in the morning time may influence dosing regimens of nifedipine for hypertension patients.

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.