Fixed combination isosorbide dinitrate-hydralazine for nitric-oxide-enhancing therapy in heart failure

The major advances in our understanding and management of heart failure (HF) in recent decades have not fully benefited all segments of our population. HF still represents a growing epidemic, especially for African-Americans, in whom the burden of HF is even greater. The recently reported beneficial effects of the fixed combination of isosorbide dinitrate and hydralazine (ISDN+HYD) in the African-American Heart Failure Trial (A-HeFT), has led to both the FDA approval of this agent and its endorsement by the latest HF guidelines. The properties of ISDN+HYD are well known as its components are mature agents, readily available in generic formulations that have been used for decades in other indications. However, fixed-dose ISDN+HYD represents the first drug to undergo targeted clinical development and to be approved for use in a specific ethnic group. As such, A-HeFT and the approval of ISDN+HYD represent landmark events that merit further scrutiny.     

Relative bioavailability of immediate- and sustained-release hydralazine formulations

The in vivo performance of hydralazine sustained-release dosage forms prepared using an ethylcellulose-coated drug:resin complex was studied in healthy males who were determined to be slow acetylators. Two studies were performed. The first study (I) compared four different coating levels (6.8, 8.7, 10, and 12%) with an immediate-release tablet and a solution. The second study (II) compared three additional coating levels (4, 5, and 7.8%) to the 6.8% formulation from the first study. Both hydralazine peak blood concentration (Cmax) and area under the blood concentration-time curves (AUC) decreased as the coating level increased [coating level (Cmax, ng/mL; AUC, ng.h/mL): 4% (37; 58), 5% (31; 55), 6.8% (13; 42 and 14; 39); 7.8% (16; 38), 8.7% (11; 34), 10% (7.8; 21), 12% (8.9; 17)]. In Study I both the solution and the immediate-release tablet were administered in two divided doses at 8 a.m. (fasting) and 2 p.m. (post-prandial). There was evidence for decreased bioavailability of unchanged hydralazine after the 2 p.m. doses as compared with the 8 a.m. doses. On the other hand, an assay that measures primarily the pyruvic acid conjugate of hydralazine yielded much higher concentrations after the afternoon dose. The results of these studies indicate that a sustained-release dosage form of hydralazine can be prepared using an ethyl-cellulose coated drug:resin complex and its in vivo characteristics are related to the coating level. Hydralazine bioavailability is influenced by food or recent prior exposure to hydralazine.     

Effects of isosorbide dinitrate spray on central hemodynamics. Comparison with sublingual glyceryl trinitrate and isosorbide dinitrate

Effects of isosorbide dinitrate (ISDN) spray (Iso Mack Spray) on central hemodynamics were determined in comparison to sublingual glyceryl trinitrate (nitroglycerin) and ISDN, paying particular attention to their onset and duration of action. In nine patients with uncomplicated acute myocardial infarction, ISDN spray (2 sprays, 2.5 mg) glyceryl trinitrate (TNG, 0.3 mg) and ordinary ISDN tablet (5 mg) were administered by the single-blind crossover method under hemodynamic monitoring with a Swan-Ganz catheter. Systolic pulmonary artery pressure (s-PA), systolic pressure (s-BP) and heart rate were measured every minute for 10 min, every 5 min for the subsequent 20 min and thereafter every 15 to 30 min up to 120 min. Using s-PA as a measure of nitrate action, the onset and duration of action as well as the magnitude of change was compared among the three drugs. ISDN spray had a quick onset of action (2.67 +/- 2.4 min, mean +/- SD) comparable to that of TNG (2.67 +/- 1.00 min), while ISDN spray had a long duration of action (57.4 +/- 42.1 min), which was comparable to that of sublingual ISDN (85.6 +/- 39.5 min, ns) and was significantly longer than that of TNG (11.4 +/- 6.4 min, p less than 0.05). ISDN spray (2.5 mg) showed the same hemodynamic changes as were induced by 0.3 mg TNG or 5 mg ISDN. The results of this study led us to conclude that ISDN spray is a useful agent which induces the abortion of anginal attacks by its quick onset and long duration of action.     

Comparative pharmacokinetics of isosorbide nitrates after repeated doses of sustained release isosorbide dinitrate

The plasma kinetics of isosorbide dinitrate (ISDN), isosorbide-5-nitrate (IS-5-N) and isosorbide-2-nitrate (IS-2-N) were investigated in 20 healthy male and female volunteers, after b.i.d. administration over 2 days of sustained release ISDN 20 mg and 40 mg capsules (Iso Mack Retard 20 mg and 40 mg) and of a 40 mg sustained release ISDN tablet as reference formulation. The means of the individual maximum ISDN concentrations during the complete 2-day treatment amounted to 10.4 ng/ml after the 40 mg capsule, 5.3 ng/ml after the 20 mg capsule and 5.3 ng/ml after the reference tablet. The corresponding figures of the metabolically generated IS-5-N were 355.5 ng/ml, 168.8 ng/ml and 161.5 ng/ml, respectively. The measured amounts of IS-5-N are expected to contribute to the overall antianginal effect of at least the 40 mg capsule. According to the b.i.d. schedule, ISDN and the two mononitrates accumulated in the plasma after all three tested formulations. However, during the treatment with the 20 mg and the 40 mg capsules, accumulation was practically completed at the second day, while it was found to be more extended during treatment with the reference product. In terms of areas under the curve, the mean bioavailability of the 40 mg sustained release capsule relative to the reference formulation was 198% with respect to ISDN, and 197% both with respect to IS-2-N and IS-5-N. On the other hand, perfect dose-linearity of all relevant pharmacokinetic parameters of all three measured isosorbide nitrates was observed for the 20 mg and the 40 mg dose of the capsule.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women

The effect of food on the oral pharmacokinetics of thalidomide and the relative bioavailability of two oral thalidomide formulations were determined in an open label, single dose, randomized, three-way crossover study. Five male and eight female healthy volunteers received a single oral dose of 200 mg Celgene thalidomide capsules under fasted and non-fasted conditions, and a single dose of 200 mg tablets of Serral thalidomide under fasted conditions. The high-fat meal resulted in a 0.5-1.5 h absorption lag time, an increased mean C(max), a decreased mean AUC and a delay in mean T(max). The Serral tablet formulation resulted in a lower mean C(max), and slower terminal decline in plasma thalidomide concentrations compared with both Celgene treatments. Mean C(max) concentrations were 1.99+/-0.41 microg/mL (range 1.28-2.76) within 4.00+/-1.13 h (2-5) for the Celgene formulation fasted, 2.17+/-0.51 microg/mL (1.43-3.01) within 6.08+/-2.33 h (3-12) for the Celgene formulation with food, and 1. 05+/-0.31 microg/mL (0.62-1.65) within 6.23+/-1.88 h (5-10) for the Serral formulation fasted. Mean terminal half-lives were 13.50+/-6. 77 h for the Serral product, compared with 5.80+/-1.72 h and 5. 09+/-1.03 h for Celgene fasted and fed, respectively. Celgene's formulation exhibited slightly greater bioavailability than Serral's formulation, with mean ratios of 122% and 110% for Ln-transformed AUC(0-t) and AUC(0-infinity), respectively. The mean C(max) for the Celgene formulation was approximately two times greater than Serral's. Food delayed the onset of absorption of by 0.5-1.5 h, but had little effect on the extent of absorption from the Celgene capsule. Under fasted conditions, the Celgene thalidomide resulted in a two-fold greater C(max) and 10% greater AUC(0-infinity) than the Serral formulation.     

The bioequivalence of liquid and freeze-dried formulations of recombinant human chorionic gonadotrophin

OBJECTIVE: To compare the bioavailability and tolerability of liquid and freeze-dried formulations of recombinant human chorionic gonadotrophin (r-hCG). SUBJECTS AND METHODS: In an open-label, randomised, single-centre, Phase I study, healthy adult volunteers (18-50 years of age) received single injections of r-hCG 250 microg from reconstituted freeze-dried (1.0 mL of 250 microg/mL) and liquid (0.5 mL of 250 microg/0.5 mL) formulations in random order, separated by a 10-day wash-out period. Pharmacokinetics (C(max), AUC, AUC(last), t(max)) and local and systemic tolerability were assessed. RESULTS: Pharmacokinetic properties of the two formulations were very similar, with mean C(max) 125 mIU/mL (liquid formulation) vs 129 mIU/mL (freeze-dried formulation), mean AUC 10,350 mIU.h/mL vs 10,480 mIU(.)h/mL, mean AUC(last) 10,050 mIU.h/mL vs 10,210 mIU.h/mL, and median t(max) 20 vs 24h. The 90% confidence intervals of the ratios of the treatment means for C(max), AUC and AUC(last) all fell within the pre-defined FDA acceptance range of 0.8-1.25, demonstrating the bioequivalence of the two formulations. Both formulations were equally well tolerated; the most frequent adverse events were headache and nausea. CONCLUSION: The liquid formulation of r-hCG was shown to be bioequivalent to the freeze-dried formulation, with no clinically significant differences in tolerability.The liquid formulation of r-hCG can be expected to provide the same efficacy and tolerability as the freeze-dried formulation when used to trigger final follicular maturation in women undergoing therapies for assisted reproduction, together with a greater convenience of use.     

Pharmacokinetics of three organic nitrates in Chinese healthy male volunteers

Eighteen Chinese male subjects completed a single-blind, randomized, three-treatment, three-period, cross-over study. In each treatment phase, subjects received a single dose of 20 mg isosorbide dinitrate (CAS 87-33-2, ISDN) intravenous infusion, 20 mg isosorbide 5-mononitrate (CAS 16051-77-7, 5-ISMN) tablet or 20 mg isosorbide 5-mononitrate intravenous infusion. Each consecutive dosing was separated by a washout period of 7 days. Following each dosing, venous blood samples were collected over a period of 16 h. Plasma concentrations of ISDN and its two active metabolites isosorbide 2-mononitrate (2-ISMN), 5-ISMN had been measured by a validated gas chromatographic method. Various pharmacokinetic parameters including AUC0-t, AUC0-infinity, Cmax, tmax, t1/2, Kelm and MRT were determined for the three formulations and found to be in good agreement with literature values. AUC0-t and AUC0-infinity of 5-ISMN tablet and intravenous infusion were 2694 +/- 496 ng x ml(-1) x h vs. 2548 +/- 556 ng x ml(-1) x h and 3266 +/- 624 ng x ml(-1) x h vs. 3178 +/- 769 ng x ml(-1) x h, respectively, and the relative bioavailability of 5-ISMN tablet was 105 +/- 20%. As compared with 5-ISMN intravenous infusion, ISDN can rapidly reach the plateau concentration and metabolize to its active metabolites 5-ISMN and 2-ISMN, which both have vasodilator effect. The results of this study suggest that as evaluated from the pharmacokinetic profiles of the three formulations, 5-ISMN tablet and ISDN intravenous infusion are ideal vasodilators and anti-angina drugs especially in acute conditions due to their rapid onset and long duration of action.     

Study on bioavailability difference between clopidogrel bisulfate form I and form II using liquid chromatography/tandem mass spectrometry

The bioavailability of clopidogrel bisulfate (CAS 135046-48-9) form I was compared with that of clopidogrel bisulfate form II in 12 male Sprague-Dawley rats. The rats, randomly divided into two groups, received a single oral dose of 8 mg/kg clopidogrel (CP) bisulfate form I and form II, respectively, under fasting condition. The plasma concentrations of CP and its inactive carboxylic acid metabolite (CAS 144457-28-3, IM) were simultaneously determined by a sensitive, specific LC-MS/MS method. The pharmacokinetic parameters included C(max), T(max), t1/2, AUC(0-t), AUC(0-infinity). The AUC(0-infinity) of CP was 13.78 +/- 0.67 and 11.46 +/- 1.98 ng/ mL x h for CP form I and form II, respectively. The AUC(0-infinity) of IM was 33.08 +/- 5.76 and 21.67 +/- 8.95 microg/mL x h for CP form I and form II, respectively. The maximum plasma concentration (C(max)) of CP was 3.81 +/- 0.54 ng/mL for CP form I and 3.18 +/- 0.31 ng/mL for CP form II, the C(max) of IM was 3.42 +/- 0.41 and 2.08 +/- 0.68 microg/ mL for the CP form I and form II, respectively. There was an obvious difference between form I and form II for C(max) and the area under the plasma concentration time curve for both CP and IM after a t-test. This study shows that CP form I has better bioavailability in rats than CP form II.     

Bioequivalence study of a sustained release fixed dose combination capsule containing esomeprazole and domperidone in healthy subjects

OBJECTIVE: The study was designed to determine the relative bioavailability of two sustained release fixed dose combination (FDC) products of two manufacturers containing esomeprazole (CAS 326602-80-6) 40 mg and domperidone (CAS 57808-66-9) 30 mg in 24 healthy male volunteers. The pharmacokinetics of esomeprazole and domperidone individually after oral administration of tablet formulation has been extensively evaluated in adult volunteers. However, no published data are available regarding the combined pharmacokinetics and bioavailability of this particular FDC. METHOD: The study was designed as a randomized, balanced, open-label, 2-period cross-over study. Each subject was randomized at the beginning of the study to receive either a single dose of the Test FDC or Reference FDC during Period I. Following a 7-day wash-out period, all subjects received the alternate formulation during Period II. RESULTS: No statistically significant differences were obtained between the two products with respect to the mean concentration-time profiles or in the pharmacokinetic parameters, including area under the serum concentration-time curve from the present study. The relative extent of absorption as assessed by the AUC ratio (Test/Reference) and C(max), the average value was found to be 1.00 +/- .09 with 90% confidence limits (C.L.) of 0.82-1.18. CONCLUSION: These findings clearly indicate that the two products are bioequivalent in terms of rate and extent of drug absorption. Both preparations were well tolerated with no adverse reactions throughout the study.     

通过体外自乳化性能及体内药代动力学评价优化葛根素自乳化制剂

本文将水不溶性药物葛根素制备成自乳化制剂。测定了葛根素在不同油相及表面活性剂的溶解度，结果表明葛根素在油酸、Tween 80中的溶解度较好，1，2-丙二醇不但能增加药物的溶解度，而且能够提高自乳化能力。以油酸为油相，Tween 80为表面活性剂，1，2-丙二醇为助表面活性剂，配制一系列混合物，通过绘制三元相图得到自乳化区，考察不同自乳化处方的自乳化性质，采用激光粒度散射仪测定乳化后粒子大小，在体外评价基础上选择较好的3个处方进行比格犬体内药动学研究，比较不同处方自乳化制剂在比格犬体内的生物利用度包括药代动力学参数Cmax， Tmax， AUC0-t。结果表明处方2和处方3的AUC0-t值［(5.201±0.511) ng·mL^-1·h， (5.174±0.498) ng·mL^-1·h］和Cmax值［(1.524±0.125) ng·mL^-1， (1.513±0.157) ng·mL^-1］显著高于处方4［(3.013±0.623) ng·mL^-1·h， (0.939±0.089) ng·mL^-1］，通过体内研究结果获得较优处方为油酸(17.5%)、Tween 80(34.5%)、1，2-丙二醇(34.5%)。自乳化释药系统提供了水不溶性药物口服给药的新途径。     

Evaluation of bioequivalence of isoniazid and pyrazinamide in three and four drugs fixed dose combinations using WHO simplified protocol.

The reliable supply of quality drugs in the form of fixed dose combination (FDC) is an essential part of tuberculosis treatment. The objective of this investigation was to evaluate whether the World Health Organization (WHO) simplified screening protocol for the bioequivalence assessment of rifampicin can be used for the evaluation of other components of FDC so as to ensure the bioavailability of all drugs at tissue site. These bioequivalence studies were conducted on 20 and 22 healthy male volunteers for evaluation of three and four drugs FDC formulations, respectively. Both studies were conducted as randomized, open, crossover trials and sampling schedule was upto 8h according to WHO recommended protocol for evaluation of rifampicin bioequivalence. The bioequivalence of isoniazid and pyrazinamide were estimated using AUC(0-8), AUC(0-alpha), and C(max). FDC formulation was considered bioequivalent to separate formulations for isoniazid and pyrazinamide if bioequivalence limit fall in between 0.80 and 1.25. Bioequivalence estimates of AUC(0-8) and AUC(0-alpha) for isoniazid and all the three pharmacokinetic measures of pyrazinamide were within the acceptable limits, whereas C(max) of isoniazid from four drugs FDC was outside the limit when evaluated by two-way ANOVA. After evaluation of isoniazid and pyrazinamide based on their pharmacokinetics, it was found that C(max) is being affected by limited sampling time points of WHO protocol. Further, AUC was a robust parameter unaffected by sampling schedule adopted. The WHO simplified protocol for assessment of rifampicin is also suitable for evaluating bioequivalence of isoniazid and pyrazinamide from FDC formulations. However, for comparison of rate of absorption by means of C(max), careful evaluation of concentration-time profile along with pharmacokinetics is necessary before final judgment.     

Bioavailability and bioequivalence of organic nitrates. Isosorbide dinitrate--a study of sustained-release preparations

Assessment of Bioavailability of Organic Nitrates/Comparative bioavailability study of sustained-release isosorbide dinitrate preparations. Relative bioavailabilities of isosorbide dinitrate (ISDN, CAS 87-33-2) and the metabolite isosorbide-5-mononitrate (IS-5-MN, CAS 16051-77-7) were studied after application of Maycor retard 40 (sustained-release capsules, multiple unit formulation, test preparation) in comparison to sustained-release tablets (single unit formulation, reference preparation) with 16 healthy male volunteers in a two-way crossover design. Test and reference formulations were previously characterised in vitro by dissolution tests. ISDN, IS-5-MN (IS-2-MN) plasma concentrations were determined using a selective and sensitive GLC-method with ECD-detection. As pharmacokinetic parameters AUC, Cmax and half value duration (HVD) were evaluated. Bioequivalence was assessed by calculating 90%-confidence intervals (ANOVA, ANOVAlog, Mann-Whitney-test) for ISDN and IS-5-MN. Bioequivalence was accepted if due to the inclusion rule one of the calculated intervals fulfill the requirements of 80 and 120% (AUC) or 70 and 130% (Cmax, HVD), respectively. Relative bioavailability of the test formulation was calculated as 94% (ISDN) and 96% (IS-5-MN). Maximum plasma concentrations of ISDN (IS-5-MN) were determined for the test preparation as 14.3 +/- 3.1 ng/ml (265 +/- 45 45 ng/ml) and as 22.8 +/- 12.6 ng/ml (287 +/- 59 ng/ml) for the reference product. HVD-values were for the test preparation 4.5 +/- 1.3 h (ISDN) and 8.5 +/- 1.3 h (IS-5-MN) and for the reference formulation 3.1 +/- 1.2 h (ISDN) and 8.1 +/- 1.4 (IS-5-MN).(ABSTRACT TRUNCATED AT 250 WORDS)     

A novel transdermal patch incorporating isosorbide dinitrate with bisoprolol: in vitro and in vivo characterization

The combination therapy of nitrate and selective beta-adrenoceptor antagonist has shown benefits for treatment of hypertension and heart disease than either drug alone. The objectives of the present study were to define effects on the anti-hypertension activity and pharmacokinetics of a novel transdermal patch incorporating isosorbide dinitrate (ISDN) with bisoprolol (BP). The 3:2 ratio of ISDN to BP (mg/mg) in the transdermal patches exhibited better anti-hypertension effect synergistically with a similar inhibiting heart rates effect to that of BP alone in renovascular hypertensive rats, and was therefore selected as a final formulation. The in vitro transdermal penetration of both ISDN and BP from the patches displayed a zero-order process, and the penetration rate constants were 7.4 microg/(cm(2)h) for ISDN, and 5.9 microg/(cm(2)h) for BP, respectively. After transdermal administration at single dose or multiple doses, the synergistic anti-hypertension effect was confirmed in spontaneously hypertensive rats also. The effect of each patch lasts for 3 days, and increased with the total dose of two drugs (2mg/cm(2), ISDN:BP=3:2, mg/mg), showing a dose dependant manner. After transdermal administration to rabbits, the absolute bioavailabilities were 33.6% for ISDN, and 31.3% for BP, respectively. The maximal concentrations (C(max)) of both drugs were significantly reduced while the areas under the plasma concentration-time curve (AUC), and mean residence times (MRT) were evidently increased and extended, respectively. As a patient-friendly, convenient, and multi-day dosing therapeutic system, the transdermal patches incorporating ISDN and BP could be promising for prevention and treatment of hypertension.     

Truncated AUCs in the assessment of the bioequivalence of topiramate, a long half-life drug

This study was conducted in order to assess the bioequivalence of two tablet formulations containing topiramate (CAS 97240-79-4), 25 mg. Twenty-four healthy volunteers were enrolled in an open-label, randomised, crossover, 2 periods x 2 sequences, with a minimum washout period of 21 days, single dose study. Blood samples were collected prior to study drug administration and 0.167, 0.333, 0.500, 0.667, 1.00, 1.33, 1.67, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 12.0, 24.0, 48.0, 96.0, 144, 192, and 264 h post-dose in each period. Plasma levels of topiramate from the 23 subjects who completed the study, were determined by high-pressure liquid chromatography with tandem mass detection, HPLC/MS/MS (lower limit of quantification 9.98 ng/mL). Pharmacokinetic parameters used for bioequivalence assessment (AUC(last), AUC(inf) and C(max)) were determined from the plasma concentration data using non-compartmental analysis. Mean +/- standard deviation elimination half-life for the reference formulation was 84.18 +/- 14.61h whereas for the test formulation it was 80.82 +/- 11.50h. The 90% Confidence Intervals (90 CI) were 98.00-111.35% for C(max), 98.44-103.76% for AUC(last) and 96.61-103.00% for AUC(inf), that is, within the ranges defined in the protocol for acceptance of bioequivalence. The 90 CIs obtained for the truncated AUCs were as follows: 100.27-105.32% for AUC0-48, 99.28-104.62% for AUC0-48, 99.13-104.56% for AUC0-96, 95.67-104.82% for AUC0-144, and 100.04-103.76% for AUC0-192. Both analysed formulations are bioequivalent irrespective of whether the conventional or truncated AUC approach is used. This study demonstrated that topiramate can be viewed as a long half-life drug and that the truncated AUC ap proach could be considered for bioequivalence assessment.     

Evaluation of "external" predictability of an in vitro-in vivo correlation for an extended-release formulation containing metoprolol tartrate

The purpose of this study was to examine the external predictability of an in vitro-in vivo correlation (IVIVC) for a metoprolol hydrophilic matrix extended-release formulation, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. In addition, this report evaluated the predictability of the IVIVC for another formulation of metoprolol tartrate differing in its release mechanism. Study 1 examined the scale up of a matrix extended-release tablet from a 3-kg small batch (I) to a 50-kg large batch (II). The second study examined the influence of scale and processing changes [3-kg small batch with fluid bed granulation and drying (III); 80-kg large batch with high shear granulation and microwave drying (IV), and a formulation with an alternate release mechanism formulated as a multiparticulate capsule (V)]. In vitro dissolution of all formulations (I-V) was conducted with a USP apparatus I at pH 6.8 and 150 rpm. Subjects received the metoprolol formulations, and serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using fluorescence detection. A previously developed IVIVC was used to predict plasma profiles. Prediction errors (PE) were <10% for C(max) and area under the curve (AUC) of concentration versus time for I, II, and IV. The C(max) for III was slightly underestimated (11.7%); however, the PE of the AUC was <10%. Formulation V displayed a PE for C(max) > 20% and an AUC within 5% of observed values. The low PEs for C(max) and AUC observed for I-IV strongly suggest that the metoprolol IVIVC is externally valid, predictive of alternate processing methods (IV), scale-up (II, III), and allows the in vitro dissolution data to be used as a surrogate for validation studies. However, the lack of predictability for V supports the contention that IVIVCs are formulation specific.     

Pharmacokinetics of isosorbide dinitrate and its mononitrate metabolites after intravenous infusion

Plasma concentrations of isosorbide dinitrate (ISDN) and its two active metabolites 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) have been measured during and for 6 hr after intravenous infusion at a rate of 2.5 mg/hr during 1.75 hr in six cardiac patients, by a capillary gas chromatographic method. Data were analyzed by simultaneous modeling of the observed kinetics of the three compounds. Two or three phases were detected on the postinfusion ISDN concentration-time curves. ISDN concentrations declined with a mean terminal half-life of 2.81 hr +/- 0.7 SD. The mean systemic clearance of ISDN (2.9 L/min +/- 0.7 SD) and its mean total volume of distribution (259 L +/- 48 SD) were relatively high. Plasma 5-ISMN concentrations were 5- to 6-fold greater than those of 2-ISMN during the whole observation period. Maximum levels of 2-ISMN (6.7 ng/ml +/- 0.9 SD) and of 5-ISMN (27 ng/ml +/- 6 SD) occurred within a few minutes after the end of infusion. The mean half-lives of 2-ISMN (1.59 hr +/- 0.19 SD) and of 5-ISMN (3.78 hr +/- 0.79 SD) estimated by the model were smaller than those calculated by a model-independent method (2.95 hr +/- 0.41 SD and 5.98 hr +/- 2.22, respectively), but were in good agreement with those reported in the literature following separate administration of both metabolites to man. This study shows how such modeling can distinguish between metabolite formation and elimination processes and allow the determination of metabolite half-lives after administration of the precursor drug.     

Kinetics of isosorbide dinitrate and relationships to pharmacological effects.

1 The inter-relationships among oral isosorbide dinitrate (ISDN) dose, drug pharmacokinetics and pharmacological effects were studied in 12 angina patients following single and chronic doses of 15, 30, 60 and 120 mg. 2 Significant accumulation of intact ISDN in plasma was observed after four times a day dosing at 30, 60 and 120 mg for 1 week. 3 The area under the plasma concentration v time curve (AUC), form 0-6 h, was shown to be proportional to dose following single doses. In contrast, AUC increased disproportionately to dose after chronic dosing. 4 Pharmacokinetic correction provided modest improvements in the dose-response relationships of ISDN. 5 Adverse hypotensive effects were observed in five patients after the single 60 mg dose. These patients showed statistically higher AUC and lower intrinsic clearance of ISDN at doses of 15, 30 and 60 mg compared to those who did not develop adverse effects. A possible relationship exists, therefore, between lower drug clearance and hypersensitivity to ISDN.     

Pharmacokinetics and bioequivalence study of clindamycin hydrochloride formulations after single-dose administration in healthy Chinese male volunteers

The aim of the present study was to compare the bioavailability of clindamycin (CAS 18323-44-9) from three clindamycin hydrochloride (CAS 21 462-39-5) capsules (clindamycin 75 mg capsule as test 1 preparation, 150 mg capsule as test 2 preparation and a commercially available original 150 mg capsule of the drug as reference preparation) in 24 Chinese healthy male volunteers, aged between 22 and 28. The study was conducted according to a randomized, double-blind, 3-period, 3-treatment, 3-sequence, single-dose, crossover design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 14 h post-dose, and clindamycin plasma concentrations were determined with a validated liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method. Maximum plasma concentrations (C(max)) of 3.06 +/- 1.10 microg/mL (test 1), 3.10 +/- 1.59 microg/mL (test 2) and 3.06 +/- 1.15 microg/mL (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 10.73 +/- 4.29 microg x h/mL (test 1), 10.54 +/- 4.10 microg x h/ mL (test 2) and 11.29 +/- 4.98 microg x h/mL (reference), AUC(0-t) of 10.32 +/- 4.09 microg x h/ mL, 10.26 +/- 3.96 microg x h/mL, 10.94 +/- 4.86 g x h/mL were calculated. The median T(max) was 0.80 +/- 0.52 h, 0.77 +/- 0.37 h, 1.01 +/- 0.6 h for test 1, test 2 and reference formulation, respectively. Plasma elimination half-lives (t1/2) of 2.72 +/- 0.58 h (test 1), 2.39 +/- 0.37 h (test 2) and 2.63 +/- 0.66 h (reference) were determined. Both primary target parameters, AUC(0-infinity) and AUC(0-t) were tested parametrically by analysis of variance (ANOVA) and relative bioavailabilities were 98.0 +/- 16.2% (test 1) and 97.2 +/- 20.3% (test 2) for AUC(0-infinity), 97.5 +/- 16.3% (test 1) and 97.8 +/- 20.2% (test 2) for AUC(0-t). Bioequivalence between test and reference preparation was demonstrated for both parameters, AUC(0-infinity) and AUC(0-t). The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%. That means that the two test formulations are bioequivalent to the reference formulation for clindamycin.     

Bioavailability and metabolism of isosorbide dinitrate from a transdermal spray.

The plasma pharmacokinetics of isosorbide dinitrate (ISDN), isosorbide-2-nitrate (IS-2-N) and isosorbide-5-nitrate (IS-5-N) were investigated in 12 healthy volunteers after a single cutaneous administration of 60 mg ISDN (CAS 87-33-2) in the form of a solution sprayed onto the skin (TD Spray Iso Mack), in comparison with an intravenous infusion of 5 mg ISDN. After the intravenous dose, the apparent steady state volume of ISDN distribution came to 179.9 l, total body clearance was 3.14 l min-1, and terminal half-life was 79 min, on average. The transdermal absorption resulted in an average peak plasma concentration of 6.9 ng ISDN ml-1 at 5 h after the administration. ISDN concentrations between 1 and 5 ng ml-1 were maintained over at least 15 h. On average, 16.5% of the topically applied ISDN reached the systemic circulation. Total variations in Cmax (CV = 47.9%) and AUC (CV = 36.0%) of transdermal ISDN were similar to those usually observed after oral ISDN.