Plasma Nifedipine Research Articles

Exploring the multiple effects of nifedipine and captopril administration in spontaneously hypertensive rats through pharmacokinetic-pharmacodynamic analyses.

This study assessed the pharmacokinetics (PKs) and pharmacodynamics (PDs) of two antihypertensive drugs, nifedipine and captopril, by exploring their main (blood pressure [BP]) and secondary effects (heart rate [HR] and QT interval [QT]) in spontaneously hypertensive rats. This study aimed to assess the relationship between PKs and PDs. Using these PD parameters, BP, HR, and QT during coadministration were estimated. The coadministration of nifedipine and captopril resulted in an increase in nifedipine's total body clearance (CLtot) and a reduction in its mean residence time (MRT) with an increase in the terminal elimination half-life (t1/2) and volume of distribution at steady state (Vdss) of captopril. However, no significant PK interactions were observed. During monotherapy, BP reduced rapidly following nifedipine infusion. Subsequently, despite the increase in nifedipine plasma concentration, BP recovered, likely because of homeostasis. Similar results were observed with coadministration. Subsequently, BP demonstrated a sustained reduction that was greater than or equal to the additive effect estimated from each PK. Captopril exhibited a minimal effect on HR, except for a transient increase observed immediately after starting infusion, consistent with observations during coadministration. Subsequently, the HR reduction was nearly equal to that calculated from the nifedipine PK. QT prolongation was more rapid with captopril than with nifedipine. Although QT prolongation during the initial 60 min of coadministration was approximately the sum of both effects, the recovery period to baseline QT was faster than that in the simulation.

Effect of repeated Shengmai-San administration on nifedipine pharmacokinetics and the risk/benefit under co-treatment.

Herbal interactions with nifedipine/felodipine through cytochrome P450 (CYP) 3A inhibition is significant in humans. Shengmai-San (SMS), a three-herbal formula of Chinese medicine, is commonly prescribed in Asia populations for cardiovascular disorders. This study aimed to elucidate the impact of SMS on nifedipine/felodipine treatment by the findings from rat pharmacokinetic study of nifedipine to the retrospective cohort study of patients with hypertension. The 3-week SMS treatment increased the systemic exposure to nifedipine by nearly two-fold and decreased nifedipine clearance by 39% in rats. Among the ingredients of SMS component herbs, schisandrin B, schisantherin A, and methylophiopogonanone A, inhibited the nifedipine oxidation (NFO) activities of rat hepatic and intestinal microsomes, as well as human CYP3A4. Methylophiopogonanone A was identified as a time-dependent inhibitor of CYP3A4. After 1:5 propensity score matching, 4,894 patients with nifedipine/felodipine use were analyzed. In patients receiving nifedipine/felodipine, the subgroup with concurrent SMS treatment had a higher incidence of headache (92.70 per 1,000 personyears) than the subgroup without SMS treatment (51.10 per 1,000 person-years). There was a positive association between headache incidence and cumulative doses of SMS (1-60 g SMS: hazard ratio (HR): 1.39; 95% confidence interval (CI): 1.11-1.74; >60 g SMS: HR: 1.97; 95% CI: 1.62-2.39; p < 0.0001). However, patients who had higher cumulative SMS doses had a lower risk of all-cause mortality (1-60 g SMS: HR: 0.67; 95% CI: 0.47-0.94; >60 g SMS: HR: 0.54; 95% CI: 0.37-0.79; p = 0.001). Results demonstrated increased rat plasma nifedipine levels after 3-week SMS treatment and increased headache incidence should be noted in nifedipine/felodipine-treated patients with prolonged SMS administration.

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.

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.

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.

Utilizing In Vitro and PBPK Tools to Link ADME Characteristics to Plasma Profiles: Case Example Nifedipine Immediate Release Formulation

One of the most prominent food-drug interactions is the inhibition of intestinal cytochrome P450 (CYP) 3A enzymes by grapefruit juice ingredients, and, as many drugs are metabolized via CYP 3A, this interaction can be of clinical importance. Calcium channel-blocking agents of the dihydropyridine type, such as felodipine and nifedipine, are subject to extensive intestinal first pass metabolism via CYP 3A, thus resulting in significantly enhanced in vivo exposure of the drug when administered together with grapefruit juice. Physiologically based pharmacokinetic (PBPK) modeling was used to simulate pharmacokinetics of a nifedipine immediate release formulation following concomitant grapefruit juice ingestion, that is, after inhibition of small intestinal CYP 3A enzymes. For this purpose, detailed data about CYP 3A levels were collected from the literature and implemented into commercial PBPK software. As literature reports show that grapefruit juice (i) leads to a marked delay in gastric emptying, and (ii) rapidly lowers the levels of intestinal CYP 3A enzymes, inhibition of intestinal first pass metabolism following ingestion of grapefruit juice was simulated by altering the intestinal CYP 3A enzyme levels and simultaneously decelerating the gastric emptying rate. To estimate the in vivo dispersion and dissolution behavior of the formulation, dissolution tests in several media simulating both the fasted and fed state stomach and small intestine were conducted, and the results from the in vitro dissolution tests were used as input function to describe the in vivo dissolution of the drug. Plasma concentration-time profiles of the nifedipine immediate release formulation both with and without simultaneous CYP 3A inhibition were simulated, and the results were compared with data gathered from the literature. Using this approach, nifedipine plasma profiles could be simulated well both with and without enzyme inhibition. A reduction in small intestinal CYP 3A levels by 60% was found to yield the best results, with simulated nifedipine concentration-time profiles within 20% of the in vivo observed results. By additionally varying the dissolution input of the PBPK model, a link between the dissolution characteristics of the formulation and its in vivo performance could be established.

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.

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.

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.

Nifedipine gastrointestinal therapeutic system (GITS) as an alternative to slow-release for tocolysis—Tolerance and pharmacokinetic profile

Objective To determine nifedipine plasma concentrations after a loading dose of nifedipine 10 mg capsules, 40 mg over 1 h followed by slow-release tablets (60 mg/d) versus gastrointestinal therapeutic system (GITS) tablets (90 mg/d) for tocolysis. Study design Prospective study in 14 pregnant women treated for threatened preterm labor. Results Following capsule administration there was a rapid rise in plasma concentration of drug achieving a peak of 97.5 μg/l (median) at 1 h, then declined to 59.5 μg/l (median) at 5 h. The concentration measured at 7200 min (120 h) was non-significantly higher in the slow-release group (median 25.5, range 6.9–67.2 μg/l) than in the GITS group (median 14.6, range 6.0–20.0 μg/l). Area under the curve (AUC) increased with the applied dose in both groups in a linear regression. Headache was more frequent in the slow-release group than in the GITS group ( P = 0.001). Conclusions GITS tablets 90 mg/d are an alternative dosage regimen to previous used slow-release tablets 60 mg/d for tocolysis with similar pharmacokinetic profile and a good tolerance. However, tocolysis with GITS tablets is simpler than that with slow-release tablets and may be associated with a higher compliance. GITS tablets are therefore also qualified for home monitoring.

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

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. Prospective clinical pharmacokinetic study. Department of Obstetrics at the Zurich University Hospital. Pregnant women treated for threatened preterm labour. GITS dosage titrated to clinical response (30-150 mg/day). Nifedipine concentrations by high-performance liquid chromatography and turbo ion spray tandem mass spectrometry. Steady-state nifedipine concentrations in maternal blood and nifedipine concentrations in maternal and corresponding umbilical cord blood at delivery. 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). 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.

Clinical and pharmacological variables as a risk factor for nifedipine‐induced gingival overgrowth

Gingival enlargement is usually noted within one to two months after the initiation of nifedipine therapy. The aetiology of nifedipine-induced gingival overgrowth is uncertain. The aim of this study was to determine the relationship between plasma and gingival crevice fluid (GCF) nifedipine concentrations and the degree of gingival overgrowth in patients treated with nifedipine, and also to assess the correlations between clinical and pharmacological variables. Eighteen patients taking nifedipine in regular doses for at least six months participated in the study. Gingival enlargement was evaluated with two indices to score vertical and horizontal overgrowth. Gingival index (GI), plaque index (PI), gingival bleeding time index (GBTI), probing depth (PD) and clinical attachment level (CAL) were also evaluated. GCF and plasma nifedipine concentrations were determined by using high performance liquid chromatography. There was no significant difference between responders and non-responders for PI, GI and GBTI. The mean concentration of nifedipine in GCF was significantly greater than concentration in plasma. No significant difference was observed for GCF and plasma nifedipine concentration between responders and non-responders. The present study showed that neither GCF nor plasma nifedipine levels appeared to be a risk factor for nifedipine-induced gingival overgrowth. Improving the oral hygiene in patients using nifedipine may help control the degree of drug-induced gingival enlargement.

Nifedipine Pharmacokinetics and Plasma Levels in the Management of Preterm Labor

The aim of this study was to determine if the dose regimen of nifedipine used for tocolysis was effective to achieve uterine quietness, and at which plasma concentration levels this tocolysis was achieved to optimize our dose regimen of nifedipine. In women with preterm labor, nifedipine was administered orally to achieve uterine quietness to prevent preterm birth. Patients (n = 5) were administered 10 mg nifedipine capsules (Adalat capsules, Bayer AG) orally every 15 minutes up to 40 mg in the first hour, and were subsequently given 1 tablet of 20 mg nifedipine slow release (Adalat retard, Bayer AG) t = 90 min. Plasma levels of nifedipine were measured at regular intervals during the first 4 hours after starting tocolysis. In all 5 patients tocolysis was achieved with nifedipine. Peak plasma concentration of nifedipine was 127.2 +/- 44 ng/mL at 1.2 +/- 0.1 hours. Mean plasma concentrations of nifedipine was 67.4 +/- 28.4 ng/mL. In all patients, tocolysis was achieved during the 4 hours of blood sampling. There were no adverse hemodynamic side effects seen before and after starting tocolysis with nifedipine. Initial dose regimen of 4 times 10 mg nifedipine capsule orally in the first hour, followed by 20 mg slow release nifedipine at t = 90 min is effective in achieving tocolysis in women with preterm labor. In steady state, the mean nifedipine plasma concentration to achieve tocolysis is about the half of that measured after initial tocolysis. Use of nifedipine for preterm labor was not associated with any adverse hemodynamic side effects.

Sensitive and simple liquid chromatographic method with ultraviolet detection for the determination of nifedipine in canine plasma

An isocratic high-performance liquid chromatographic method with detection at 240 nm was developed, optimized and validated for the determination of nifedipine in canine plasma. Liquid–liquid extraction was used as the sample preparation technique. Carbamazepine was used as internal standard. A Hypersil BDS RP-C 18 column (250 mm × 4.6 mm, 5 μm) was equilibrated with a mobile phase composed of water and methanol, 45:55 (v/v). Its flow rate was 1 ml min −1. The elution time for nifedipine and carbamazepine was approximately 12 and 8 min, respectively. Calibration curves of nifedipine in plasma were linear in the concentration range of 1–200 ng ml −1. Limits of detection and quantification in plasma were 0.5 and 1.5 ng ml −1, respectively. Recovery was greater than 98%. Intra- and inter-day relative standard deviation for nifedipine in plasma was less than 8.5 and 10%, respectively. This method was applied to the determination of nifedipine plasma levels after administration of commercially available soft gelatine capsules to dogs.

Modified-Release Nifedipine

Nifedipine is a dihydropyridine calcium channel antagonist with predominantly vasodilatory activity. Modified-release formulations of nifedipine are effective antihypertensive and antianginal therapies and are generally well tolerated. Among the available formulations, those that produce a gradual increase in plasma nifedipine concentration, which is then sustained over a 24-hour period, are preferred, as they cause a gradual onset of vasodilatation and avoid baroreflex sympathetic activation (for example, nifedipine gastrointestinal therapeutic system [GITS] and a Japanese controlled-release formulation). Modified-release nifedipine had beneficial effects on a number of markers of vascular function, and nifedipine GITS reduced the need for coronary procedures in patients with coronary artery disease. In patients with hypertension, nifedipine GITS and nifedipine retard had beneficial effects on the overall incidence of major cardiovascular events, as did nifedipine retard in patients with concurrent hypertension and coronary artery disease.

Clinical Experience with Nifedipine in the Treatment of Angina Pectoris in Japan

Developed by Bayer in Germany, nifedipine was shown to be effective in the treatment of patients with angina pectoris by Japanese investigators. Professor Kimura first reported the efficacy of nifedipine in patients with angina pectoris and those findings have been replicated in numerous trials conducted since then. Clinical trials found a low incidence of fixed coronary artery stenosis in Japanese patients with variant angina pectoris, and a complete antianginal response with Ca2+ channel antagonist such as nifedipine. It was hypothesised that the mechanism of this benefit with nifedipine was because of a strong coronary vasodilating action along with an inhibitory effect on coronary spasm. Recent evidence has established the tolerability and efficacy of once-daily dosage forms, which provide stable plasma nifedipine concentrations, in the management of coronary artery disorders.

Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union

The objective of this study was to compare the rate and extent of nifedipine bioavailability after single dose administration of Adalat OROS 30 (Reference) and Nifedipine Sandoz retard 30 tablets (Test). Both modified release formulations are marketed in Member States of the European Union. Prior to the clinical study the in vitro dissolution characteristics were investigated. There was a significant pH dependency observed with the Test product but drug release with the Reference product was almost independent of the experimental conditions used. In the subsequent open, randomized, controlled, 4-way crossover study both pharmaceutical products were administered to 28 healthy male volunteers, either after fasting overnight or immediately after a high-fat American breakfast. Blood sampling was performed over 48 hours post-dose for the determination of pharmacokinetic profiles of nifedipine. Considerable differences were observed between the two formulations when administered to fasted subjects where maximum nifedipine plasma concentration (C(max)) were higher in the case of the Test formulation. Differences were even more pronounced after a high-fat American breakfast. Under these conditions a significant food interaction was detected in the case of Nifedipine Sandoz retard 30 with a three-fold increase in the mean C(max) when compared to values obtained in fasting subjects. In contrast, food intake had no clinically relevant effect on bioavailability of nifedipine (rate and extent) in the case of Adalat OROS 30. The pharmacokinetic findings in this study were reflected in the adverse event pattern which indicated a potential tolerability problem in the case of Nifedipine Sandoz retard 30. The results confirm the relationship between the in vitro dissolution profile results and the effects of the drug in vivo. Dose dumping after intake of a high-fat meal could be shown. Nifedipine Sandoz retard 30 is not bioequivalent to Adalat OROS 30 and produced highly variable and poorly predictable nifedipine plasma concentrations. The differences observed between the two products investigated may have direct therapeutic relevance when switching from one formulation to the other and, in particular, when administration conditions change i.e. administration in the fasting state and administration with a meal, since the pharmacological and therapeutic actions of nifedipine are closely associated with the concentration.

Clarithromycin—Nifedipine Interaction as Possible Cause of Vasodilatory Shock

To report a case of vasodilatory shock possibly resulting from a clarithromycin-nifedipine interaction. A 77-year-old male with uncontrollable hypertension developed shock, heart block, and multiorgan failure 2 days after clarithromycin was added to his antihypertensive treatment (nifedipine, captopril, doxazosin). Invasive monitoring revealed hyperdynamic shock with decreased systemic vascular resistances. Nifedipine is metabolized by isoenzyme CYP3A4. This metabolic pathway is inhibited by clarithromycin, thus potentially increasing the plasma nifedipine concentration, which may lead to excessive calcium-channel blocker effects. Clinical manifestations of excessive calcium-channel blockade comprise hypotension or vasodilatory shock and heart block, as in our case. An objective causality assessment revealed that this drug interaction was the possible cause of these adverse effects. Because of an initial diagnosis of septic shock, suspicion of this entity was delayed and specific diagnostic and treatment were not possible. This life-threatening clinical picture, including shock and heart block, was possibly the result of a pharmacokinetic interaction between clarithromycin and nifedipine.

Time-release compression-coated core tablet containing nifedipine for chronopharmacotherapy

Compression-coated time-release tablets (CC tablets) containing nifedipine, dihydropyridine Ca channel blocker, in the core tablet were prepared by dry coating with different polyethylene oxide-polyethylene glycol mixtures. Each formulation showed a clear lag period before nifedipine release initiation, followed by sustained drug release lasting up to 24 h. The lag time of nifedipine release increased as the amount of polyethylene oxide in the outer layer increased. To investigate the applicability of such CC-tablets for chronopharmacotherapy, the pharmacokinetics of CC-1 and CC-2 tablets, with different in vitro lag times before drug release, were compared with the pharmacokinetics of a sustained-release (SR) tablet in dogs. The times of first nifedipine appearance (TFA) in plasma were 0.7 ± 0.3 h for SR, 2.5 ± 1.2 h for CC-1, and 5.3 ± 1.0 h for CC-2. These data show a significant difference in in vivo lag time ( P < 0.01) among the three formulations that correlates with the in vitro lag times. Thus, the in vivo lag time could be predicted from the in vitro lag time. Additionally, higher plasma nifedipine concentrations were observed at 8 h after administration of the CC-2 than that observed for the SR-tablet. These results indicate that a CC-tablet with a lag time before drug release is a potentially useful formulation for chronopharmacotherapy that can control the time and duration of plasma drug concentration better than existing SR technologies.