Pharmacokinetics of isosorbide dinitrate after intravenous infusion in human subjects

Plasma concentrations of isosorbide dinitrate have been measured after intravenous infusion of drug at a rate of 5·0 mg h^?1 for 150 min and after single equal oral doses of 12·5 mg of drug in solution to two normal human subjects. During the infusion, uneven plateau concentrations were approached after 30 min. The calculated average steady-state plasma levels were 258 ng ml^?1 and 514 ng ml^?1 in the two subjects respectively. The half-life of elimination of isosorbide dinitrate after termination of the infusion was 9–10 min. After oral doses, peak plasma levels of 26·6 ng ml^?1 and 12·7 ng ml^?1 occurred at 10 min and 20 min in the two subjects respectively. The terminal half-life of drug after the oral doses was much longer than the elimination half-life (about 10 min), and was associated with the absorption phase. Fairly good agreement was obtained between the observed concentrations and those predicted by a one-compartment open model. The systemic availability of isosorbide dinitrate after the oral doses was up to only 3 per cent of the equal doses infused, indicating that presystemic elimination processes accounted for very large proportions of the oral doses. The systemic clearances of drug after infusion of 0·32 1 min^?1 and 0·161 min^?1 were unexpectedly low for a drug of reported high liver extraction ratio.     

Plasma concentrations and bioavailability of isosorbide dinitrate and pindolol from a combination formulation

The plasma concentrations and bioavailability of sustained-release isosorbide denigrate and standard-release pindolol have been compared after administration of these drugs in combination and alone. Bioavailability parameters of isosorbide dinitrate and pindolol obtained after administration of the drugs in combination were not significantly different (P>0.05) to those obtained after administration of either drug alone. Two peaks of mean concentrations of isosorbide dinitrate occurred in plasma after administration of 30 mg of this drug in combination with 7.5 mg pindolol (4.4 ng ml^?1 at 1 h and 4.5ng ml^?1 at 5h), or alone (5.9ngml^?1 at 2h and 5.7ng ml^?1 at 5h). In each case, plasma concentrations of isosorbide dinitrate were maintained during at least 8 h, whereas the drug was not detected in plasma at 2.5 h after administration of a standardrelease formulation. The peaks of mean concentrations of pindolol were 39.7ng ml^?1 at l.5h after administration of 7.5 mg drug in combination with isosorbide dinitrate and 38.0 ng ml^?1 at 1 h after administration of the drug alone. Concentrations of pindolol in plasma declined with a half-life of 3 h.     

Measurement of plasma concentrations of isosorbide dinitrate

Concentrations of the vasodilator isosorbide dinitrate (ISDN) in human plasma can be measured with good sensitivity (about 0·2–0·5 ng ml^?1) using electron-capture gas chromatography after a one-stage extraction. The mean recovery of ISDN from plasma was 83 per cent ± 9 standard deviation (S.D.). The precision of the method for the measurement of ISDN in plasma ranged from ± 14 per cent at 1 ng ml^?1 to ± 7 per cent at 5 ng ml^?1 to ± 4 per cent at 50 ng ml^?1. The 95 per cent confidence limits of the least-squares regression calibration line forced through the origin were ± 100 per cent at 1 ng ml^?1, ± 11 per cent at 10 ng ml^?1, and ± 8 per cent at 30 ng ml^?1. The method has been used to assay many samples withdrawn after doses of drug at therapeutic levels to normal subjects.     

Radioimmunoassay of the new opiate analgesics alfentanil and sufentanil. Preliminary pharmacokinetic profile in man

The development of two analogous radioimmunoassay (RIA) procedures based on dextran-charcoal separation is described for the quantification of two fentanyl-like analgesics, alfentanil and sufentanil. Immunization of rabbits with conjugates of bovine serum albumin and carboxy-derivatives of the respective drugs resulted in the production of antisera capable of detecting less than 0.05 ng ml^?1 of the parent analgesics with high specificity and almost no cross-reactivity with major metabolites. Excellent agreement was obtained between RIA—without prior extraction—and gas chromatography for alfentanil concentrations in human plasma. Because of sufentanil's low therapeutic plasma levels, no comparison could be made between its RIA and an alternative assay, however, there was strong evidence for the specificity of the assay when applied directly to plasma. With these RIA methods preliminary information was obtained on plasma concentrations and elimination of alfentanil or sufentanil in patients given an intravenous bolus injection of 50 μg kg^?1 of alfentanil, or 5 μg kg^?1 of sufentanil. For both analgesics, the pharmacokinetic profile in man could be described by a three-compartment model. The terminal elimination half-life was 88 min for alfentanil and 140 min for sufentanil. Six hours after a therapeutic dose, plasma levels were in the order of 3 and 0.3 ng ml^?1 for alfentanil and sufentanil respectively.     

Myocardial Pharmacokinetics and Pharmacodynamics of Nifedipine in the Isolated Rabbit Heart

Abstract: The myocardial accumulation and disposition pharmacokinetics of the antianginal and antihypertensive calcium-antagonistic drug nifedipine were investigated in isolated, perfused and spontaneously beating rabbit hearts. The myocardium behaved pharmacokinetically as a two-compartment system with regard to the drug. The mean half-lives of the α-phase of distribution and of the β-phase of disposition were about 1.2 and 6.5 min., respectively. Perfusion with a modified Krebs-Henseleit solution containing nifedipine in a concentration of 50 ng ml^?1 caused an accumulation of about 1277 ng g-1 in the myocardium at steady state. Stepwise increased concentrations of nifedipine from 3 to 60 ng ml^?1 in the liquid used in perfusions for 25 min. periods produced a pronounced progressive decrease in myocardial contractility to about 8%. The heart beating frequency simultaneously decreased gradually to about 76%. The mean coronary flow rate increased initially to 135% and then gradually decreased to 94%. These effects were accompanied by a decrease to about 0.27 in the ratio of the product of contraction amplitude and frequency to the oxygen consumption, a finding that was evaluated as an expression of reduced myocardial efficiency. No significant dromotropic effects were observed.     

Isosorbide 5-mononitrate pharmacokinetics in humans

When isosorbide 5-mononitrate was intravenously infused at a rate of 4 mg h ^?1 for 2.5 h to five human subjects, its concentrations in plasma increased slowly to 185 ng ml^?1 ± 5 per cent C.V. at 2.5 h and a steady-state plasma level was not reached during the infusion. When the infusion was discontinued, plasma drug concentrations declined with an elimination half-life of 4.2 h ± 6 per cent C.V. The systemic clearance after the infusion doses was 132 ml min^?1 ± 18 per cent C.V. and the volume of distribution was 48.4 1 ± 16 per cent C. V. After equal oral doses of 10 mg, the peak plasma isosorbide 5-mononitrate concentration of 191 ng ml^?1 ±16 per cent C.V. was reached at 1.1 h ± 30 per cent C.V., and plasma levels declined with a terminal half-life of 4.9 h. The complete systemic availability of isosorbide 5-mononitrate indicated that pre-systemic elimination after the oral doses was negligible. A one-compartment open model appeared adequate to describe the plasma level data after intravenous infusion and oral doses. After single oral doses of 10 mg isosorbide dinitrate, the peak plasma concentration of the 5-mononitrate metabolite of 72 ng ml^?1 ± 27 per cent C. V. occurred at l.7h.41 per cent C.V. Approximately 50 per cent (range 22–68 per cent) of the oral dose of isosorbide dinitrate circulated in plasma as the 5-mononitrate metabolite. The pharmacokinetics of isosorbide mononitrates are markedly different to those of the parent dinitrate and these differences follow from the greater systemic availability and volume of distribution of the mononitrates.     

Bioavailability of nifedipine: A comparison between two preparations

In a random cross-over study, eight healthy volunteers received single 10 mg doses of either nifedipine capsule (Adalat, Bayer) or nifedipine tablets (Taro) after an overnight fast. The areas under the serum concentration time curves were not significantly different (AUC^{0→ ∞} 319·8 ± 28·0 (SEM) ng ml^?1 h^?1 for capsules, 260·8 ± 15·3 ng ml^?1 h^?1 for tablets). The peak serum levels and the time of their occurrence were 162·4 ± 23·4 ng ml^?1 at 30 min for capsules and 43·0 ± 3·0 ng ml^?1 at 1–2 h for tablets, indicating that the absorption of nifedipine from the capsule is faster than from the tablet form. Clinical symptoms of vasodilation corresponded with the nifedipine peak levels. We conclude that although the bioavailability in general of the two preparations is similar, the therapeutic equivalence may differ. Depending on the therapeutic indication each preparation may have its merits.     

The pharmacokinetic assessment of sodium cromoglycate

The plasma concentration of sodium cromoglycate (SCG) was measured in four healthy subjects by radioimmunoassay after a 4 mg intravenous dose and after inhaling from 20 mg capsules, and from 10 and 30 mg ml^?1 nebulizer solutions. The mean absorption constant (K₁) after inhalation was 0·43 h^?1. The mean elimination constant from the plasma (K_elim) after intravenous administration was 11·5 h^?1, and that after inhalation was similar. The apparent volume of distribution of SCG (V_dβ) was 0·2 litre kg^?1 and the mean plasma clearance was 0·35 litre h^?1kg^?1. The amount of SCG absorbed after inhalation varied according to the method of inhalation and dose. After the inhalation of powder from 20 mg capsules, 1·30–3·96 mg reached the plasma, after inhalation of SCG produced by nebulizing a 10 mg ml^?1 solution for 5 min at 10 psi using a Minineb nebulizer 0·19—0·31 mg reached the plasma and when the solution was increased to 30 mg ml^?1 the figure was 0·33—0·45 mg.     

Quantitation of iprindole in plasma by GLC

A specific, sensitive, rapid, and reproducible method for iprindole in human plasma was developed using gas chromatography with trimipramine as internal standard. The sensitivity of the method is of S ng ml^?1 and a linearity was obtained for concentrations ranging from 12.5ngml^?1 to 100ngml^?1 with a regression coefficient of 0.9872. The plasma levels of iprindole were determined in five healthy volunteers following the administration of a single oral dose of 60 mg and in four patients admitted for endogenous depression after a 3-week administration of 90mgd^?1. Following a single oral dose to healthy volunteers, the maximum concentrations occurred between 2 and 4h after administration of the drug and the mean half-life value was 52.5 h. In patients the steady-state concentrations of iprindole ranged between 18 and 77ngml^?1.     

Two metabolites of sulphinpyrazone and their identification and determination by mass spectrometry

Sulphinpyrazone is an antiplatelet agent in vivo and in vitro. Two active metabolites, a sulphide (S) and a hydroxylated sulphide (S-OH) have been identified in rabbit and human plasma and a selective and sensitive g.c.-m.s.-method for quantitative determination of the sulphide and hydroxylated sulphide in plasma and urine has been evolved which allows concentrations down to 5 ng ml^?1 for the sulphide and 30 ng ml^?1 for the hydroxylated sulphide to be detected. The time course of the metabolite concentrations in plasma corresponds to the biological findings, suggesting that the metabolites contribute significantly to the in vivo effects of the drug.     

Pharmacokinetics of acetylmethadols I: Gas-liquid chromatographic determination of L-α-acetylmethadol and its major metabolites in plasma

A gas chromatographic method is reported for simultaneously determining acetyl-methadol, noracetylmethadol, and dinoracetylmethadol in plasma. Minimum detectable concentrations are 10 ng ml^?1 for acetylmethadol using a flame ionization detector, and 5 and 25 ng ml^?l for noracetylmethadol and dinoracetylmethadol respectively using electron capture detection. Extraction efficiency is quantitative for acetylmethadol but lower for the metabolites. The method is useful for monitoring drug levels following therapeutic doses of acetylmethadol.     

The effect of carbenicillin on the haemostatic mechanism

Carbenicillin has no effect on the thrombin time, partial thromboplastin time, prothrombin time, platelet factor 3 availability, fibrinogen and plasminogen levels, Factor XIII, fibrin plate lysis or euglobulin lysis time in vitro in concentrations from 20–1280 μg ml^?1. After incubation with plasma, carbenicillin inhibited platelet aggregation to ADP at all the concentrations examined (20–1280 μg ml^?1). The same coagulation tests were unaffected 30 min and 4 h after intravenous administration of 5 g of carbenicillin to six normal subjects, though some impairment of platelet response to ADP occurred in three subjects. This impairment of platelet function is considered unlikely to contribute towards a bleeding tendency in normal subjects but might perhaps be a contributory factor in haemostatic failures in patients with uraemia.     

LC separation and induced fluorometric detection of rivastatin in blood plasma

An LC procedure suitable for quantitative analysis of pg ml⁻¹ concentrations of the HMG-CoA reductase inhibitor rivastatin in blood plasma was developed. The procedure involves an extraction step, chromatography on an ODS column, and fluorometric detection of a post-column photolytic decomposition product that was isolated and identified. The achieved quantitation limit (25 pg ml⁻¹) facilitated analysis of relatively low rivastatin concentrations in plasma that were observed after 100–300 μg oral doses of rivastatin. At 25 pg ml⁻¹ concentration the RSD ranged from 3.6 to 13.5% and mean deviation from the nominal value was 8.0%; at 8 ng ml⁻¹ the RSD range was 0.7–3.6% while the mean deviation was −1.8%. The concentrations obtained with the LC procedure were compared to the concentrations obtained with a specific but less sensitive capillary GC method and a radioimmunoassay (RIA) procedure. Concentrations obtained with the HPLC and GC procedures agreed within experimental error; the RIA concentrations were about 30% higher.     

Bioavailability of a commercial sustained-release quinidine tablet compared to oral quinidine solution

The bioavailability of quinidine sulfate after oral administration of a commercial sustained-release quinidine tablet was compared with that of oral quinidine sulfate solution in 18 normal subjects. Three hundred milligrammes of each product was administered to each subject in standard cross-over fashion on separate occasions, with plasma quinidine levels measured for 46 h after each dose. Although peak plasma quinidine levels were lower, and occurred later, after tablet administration than after solution, analysis of the area under the plasma quinidine level-time curve (AUC) values for each product indicated that the products were equivalent, in terms of the extent of absorption, with the mean AUC (0–46h) value for the tablet, 8744.4 ng × h ml^?1, comparable to that of the solution, 9145.9 ng × h ml^?1.     

A New Method for the Measurement of Nitrosoureas in Plasma: an H.P.L.C. Procedure for the Measurement of Fotemustine Kinetics

1. An analytical method for a novel nitrosourea, fotemustine, has been developed using solid-phase extraction and?h.p.l.c. with u.v. detection. As part of the development, different methods for stabilising fotemustine after sample collection have been investigated. The method has been successfully applied to pharmacokinetic studies in monkeys and man.

2. Providing plasma was separated immediately from blood and frozen within 3?min of collection, negligible degradation of fotemustine occurred. The samples could then be stored at —20°C in the dark for up to six days particularly if thawing prior to analysis was accelerated using a 50°C water-bath so that it was complete within 3?min. Equivalent results were also obtained with samples stabilised with 0·1?m citric acid immediately after the preparation of plasma.

3. The analytical method showed good precision with a within-day variation ranging between ±10.7% at the lowest concentration investigated (0.1 μg ml^?1) to 2.0% at 50.0 μgml^?1. The accuracy of measurement was from 108.9% to 97.6% at 0.1 and 50.0 μg ml^?1 respectively and the response was linear up to 50 μg ml^?1. The minimum level of quantitation was 20 ng ml^?1.

4. After a single intravenous bolus dose of [¹⁴C]fotemustine (100mg m^?2) to Cynomolgus monkeys, intact drug levels rapidly declined (t_1/2 12.6±0.5?min) although the halflife of radioactivity (approx 100?h) was much longer. The plasma clearance of fotemustine was 225±63 ml min^?1 with a volume of distribution based on area of 4.1±1.2 litres.

5. As with monkey, plasma levels of intact fotemustine in a patient given [¹⁴C]-drug as a 1?h constant rate intravenous infusion (approx. 100?mg m^?2), declined rapidly but with a half-life of 23.2?min. Again, the half-life for total radioactivity was considerably longer (30.8?h). The plasma clearance was 1426 ml min^?1 and the volume of distribution based on area was 47.71.     

LC-MS-MS analysis of 2-pyridylacetic acid,a major metabolite of betahistine: application to a pharmacokinetic study in healthy volunteers

1.?A sensitive liquid chromatographic-tandem mass spectrometric assay was developed and validated to determine the major metabolite of betahistine, 2-pyridylacetic acid, in human plasma.

2.?The analyte was extracted from plasma samples by liquid–liquid extraction and analysed using liquid chromatography-tandem mass spectrometry with an electrospray ionization interface. The method has a lower limit of quantitation of 1?ng?ml^?1 for a 0.5-ml plasma aliquot. The intra- and interday precision (relative standard deviation), calculated from quality control (QC) samples, was less than 10%. Accuracy as determined from QC samples was within ±7%.

3.?The validated method was successfully applied to a pharmacokinetic study of betahistine in healthy volunteers. After oral administration of a single dose of 24?mg betahistine mesylate to 20 healthy Chinese male volunteers, C_max was 339.4?ng?ml^?1 (range 77.3–776.4?ng?ml^?1). The t_1/2 was 5.2?h (range 2.0^?1?11.4?h). The AUC_0?t obtained was 1153.5?ng?ml^?1?h (range 278.5–3150.8?ng ml^?1?h). The disposition of the metabolite exhibited a marked interindividual variation.

4.?The plasma concentrations of the parent drug were less than 0.5?ng ml^?1, suggesting that it undergoes almost complete first-pass metabolism. The reported two active metabolites were not detected in the plasma of any volunteer. Although there is no evidence that the major metabolite has pharmacological activity, the clinical importance of 2-pyridylacetic acid in humans should be reinvestigated.     

Simplified reversed-phase HPLC method with spectrophotometric detection for the assay of verapamil in rat plasma

A high-performance liquid chromatographic (HPLC) method was developed for the assay of verapamil in rat plasma. After deproteinization of the plasma sample with an acetonitrile-perchloric acid (8:2) mixture containing dextromethorphan, the internal standard, an aliquot of the supernatant was directly analyzed on a cyanopropylsilane column with methanol-acetonitrile-triethylamine acetate buffer (10:30:60) as the mobile phase and detection at 235 mm. At a flow rate of 1.5 ml min⁻¹, a complete analysis was completed in less than 6 min. The method was linear for verapamil concentrations in the range 0.5–10 μg ml⁻¹ (r=0.9999). Recoveries for the same drug concentrations from spiked rat plasma ranged from 85.6-93.0% (n=8). The mean RSD values for intraday and interday assay reproducibility (n=3) were, in both cases, less than 0.9%. The limit of detectability was about 0.1 μg ml⁻¹. The method was found useful to monitor the plasma levels of verapamil in rats that had received this drug by the nasal, oral and intravenous routes of administration.     

In vitro effect of nickel on bovine spermatozoa motility and annexin V‐labeled membrane changes

In this study the effect of in vitro culture of bovine spermatozoa with nickel (NiCl₂) on spermatozoa motility and membrane changes was analyzed. The spermatozoa motility significantly decreased after 120 min of culture at the concentration of 1000 μm Ni ml^?1 (P < 0.05) and after 240 min of culture at the concentration of 500 and 1000 μm Ni ml^?1 (P < 0.001) as compared with control. The progressive motility was the highest in the control group and in the groups with the lowest nickel concentrations (7.8 and 125 μm Ni ml^?1). The progressive spermatozoa motility was significantly altered even after 30 min of culture in the group with the highest nickel concentration (1000 μm Ni ml^?1). A significant decrease in progressive motility from the concentration of 250 μm Ni ml^?1 was detected after 240 min of culture. Concentrations from 125 μm Ni ml^?1 in various time periods of culture stimulated spermatozoa motility after 30 min (P < 0.001), but later an inhibitory effect was noted. After 240 min of in vitro spermatozoa culture with 125 μm Ni ml^?1 a typical Annexin V fluorescence reaction was detected. Fluorescence was detected in mitochondrial segment of bovine spermatozoa. In spermatozoa exposed to higher nickel concentrations the Annexin V‐positive reaction was detected also on the spermatozoa head membrane. In the group with the highest concentration and the longest time of exposure (1000 μm Ni ml^?1; 240 min) the apoptotic Annexin‐positive regions were detected not only in the mitochondrial part, but also in the spermatozoa head (acrosomal and postacrosomal part), showing significant alteration of spermatozoa membrane integrity. Copyright © 2010 John Wiley & Sons, Ltd.     

Simple HPLC Determination of the Concentrations of Epiroprim in the Serum and Brains of Mice

Epiroprim, an analogue of trimethoprim, has been shown to potentiate the efficacy of dapsone in experimental parasitic infections. A simple and accurate HPLC method has been developed to estimate epiroprim in serum and brain Blood and brains from mice were sampled 0, 30, 75, 120 and 240 min after 50 or 100 mg kg^?1 oral gavage. The drug and added internal standard metoprine in serum and brain supernatant were isolated by solid-phase extraction (Supelclean LC-SCX). The HPLC system consisted of a 150 × 4.6 mm Hypersil 5 μm ODS column. The mobile phases contained various proportions of acetonitrile, methanol and phosphate buffer (0.1 M). Peaks were detected by UV absorbance at 210 run. Serum concentrations (mean ± s.e.m.) of epiroprim were highest at 30 min for both 50 and 100 mg kg^?1 doses, 173 ± 20 and 207 ± 25 ng mL^?1, respectively, falling to 8 ± 5 and 18 ±6 ng mL^?1, respectively, at 240 min. Epiroprim concentrations in the brain correlated well with those in the serum, with levels of 223 ±69 and 265 ±21 ng g^?1 falling to 10 ± 10 and 31 ± 11 ng g^?1, respectively. Epiroprim is rapidly absorbed and distributed to the brain.     

Assessment of the value of therapeutic monitoring of tacrine in Alzheimer's disease

Objectives: The purpose of this study was to validate the lower end of the putative therapeutic range of serum tacrine concentrations of 7–20?ng?·?ml^?1 in the treatment of Alzheimer's disease. Methods: The relationship between dose, steady-state serum tacrine concentrations and change in MMSE score (a measure of cognitive function) was examined in 106 Alzheimer's disease patients who had been treated with the drug for 12 weeks. Results: In all, 72% of patients showed some response, but there was no relationship between dose and the chance of a favourable outcome. The proportion of patients with serum concentrations above 7?ng?·?ml^?1 who improved (79%) was significantly greater than that of those with serum concentrations below this level (47%) (P?<?0.02). Also, a significantly greater proportion of patients with serum concentrations above both 5?ng?·?ml^?1 and 9?ng?·?ml^?1 showed improvement in comparison to those with concentrations below these levels. Conclusions: This study indicates that therapeutic monitoring of serum tacrine concentrations might increase the possibility of responding to tacrine by some 68%. This represents an important contribution to the management of Alzheimer's disease patients with this drug, and may also be relevant to the use of the newer generation of cholinesterase inhibitors.