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L F Chasseaud

Publications and source records attributed to L F Chasseaud.

At least 181 records · Page 10Linked to original sources
PubMedDate not supplied

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 percent 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 The method has been used to assay many samples withdrawn after doses of drug at therapeutic levels to normal subjects.

Chromatography, Gas↗
PubMedDate not supplied

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 l min-1 and 0.16 l min-1 were unexpectedly low for a drug of reported high liver extraction ratio.

Adult↗
PubMedDate not supplied

Concentrations of N-descyclopropylmethylprazepam in whole-blood, plasma, and milk after administration of prazepam to humans.

After oral doses of 30 mg of prazepam to humans, N-descyclopropylmethylprazepam (desalkylprazepam, N-desmethyldiazepam) is the only major drug-related compound in plasma. Neither the parent drug, nor its major urinary metabolites were detected in plasma. The overall concentration-time profile of desalkylprazepam in the plasma of females was lower than, and significantly different (p less than 0.001) from that in the plasma of males. However, the mean peak desalkylprazepam concentrations in the plasma of females (265 ng ml-1 +/- 60 S.D.) were not significantly different (p greater than 0.05) from those in males (342 ng ml-1 +/- 60 S.D.). Concentrations declined in the plasma of either sex with similar half-lives (mean 60 h, range 37-93 h). Apparent plasma desalkylprazepam clearances were also similar (mean 60 h, range 37-93 h). Apparent plasma desalkylprazepam clearances were also similar (mean 1.09 l h-1), range 0.74-1.84 l h-1). At 12 h after the last of multiple doses of prazepam (60 mg d-1 for 3 days) to lactating women, mean plasma concentrations of desalkylprazepam were 823 ng ml-1 +/- 200 S.D. and declined with a mean half-life of about 60 h over the time-course studied. There was only slight uptake of desalkylprazepam into blood cells; plasma; whole blood concentration ratios were constant at about 1.6. Concentrations of desalkylprazepam in milk were low at about 10 per cent of the corresponding plasma levels (e.g. 86 ng ml-1 +/- 37 S.D. at 12 h). The data suggest that, expressed on a mg kg-1 basis, exposed neonates could receive about 4 per cent of the maternal dose of prazepam as desalkylprazepam.

Administration, Oral↗
PubMedDate not supplied

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 +/- 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 dose. 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 1.7 h +/- 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.

Adult↗
PubMedDate not supplied

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

The plasma concentrations and bioavailability of sustained-release isosorbide dinitrate 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 greater than 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 4.5 ng ml-1 at 5 h), or alone (5.9 ng ml-1 at 2 h and 5.7 ng ml-1 at 5 h). 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 standard-release formulation. The peaks of mean concentrations of pindolol were 39.7 ng ml-1 at 1.5 h after administration of 7.5 mg drug in combination with isosorbide dinitrate and 38.0 ng ml-1 at 1 h administration of the drug alone. Concentrations of pindolol in plasma declined with a half-life of 3 h.

Adolescent↗
PubMedDate not supplied

Bioavailability of bemetizide and triamterene from a combination formulation.

The bioavailability of the thiazide diuretic bemetizide from a tablet containing 25 mg of this drug and 50 mg of the chemically unrelated diuretic triamterene was lower than, and significantly different (p less than 0.01) from that from a tablet containing 25 mg bemetizide alone. The mean peak plasma level of bemetizide after administration of the combination tablet (68.3 ng ml-1) was lower than that after administration of bemetizide alone (87.9 ng ml-1), although the times of occurrence of the peak levels were similar. The bioavailability of triamterene from the combination tablet was greater than, but not significantly different from that after administration of a capsule containing 50 mg triamterene alone. The mean peak plasma level of triamterene after administration of the combination tablet (44.6 ng ml-1) was higher than and significantly different (p less than 0.001) from that after administration of triamterene alone (15.7 ng ml-1). Although bemetizide is unstable in urine, measurement of the apparent excretion of unchanged drug in the 24 h post-dose urine (less than 4 per cent of the dose) agreed with the estimate of drug bioavailability from the plasma level data. Less than 2 per cent of the dose of triamterene was excreted unchanged in the 24 h post-dose urine, but the urinary excretion data also agreed with the bioavailability estimates from the plasma level data. The results of this study and those reported in the literature suggest that because of their physicochemical properties, the bioavailability of some thiazides and triamterene needs to be evaluated when new formulations of these drugs are produced. However, with respect to the combination formulation reported in this paper, the difference in bioavailability of the thiazide component did not detectably effect the diuretic activity of the formulation.

Adolescent↗
PubMedDate not supplied

Bioequivalence of a sustained-release isosorbide dinitrate formulation at steady-state.

Isosorbide 2,5-dinitrate and its pharmacologically active metabolites, isosorbide 2-nitrate and isosorbide 5-nitrate, in plasma accumulated to the predicted steady-state after five consecutive oral doses of sustained-release tablets containing 40 mg isosorbide dinitrate at 12-h intervals and after five consecutive oral doses of reference standard-release tablets containing 20 mg at 6-h intervals to 12 subjects in a crossover study. The comparative bioavailability of isosorbide dinitrate, isosorbide 2-nitrate and isosorbide 5-nitrate from the sustained-release tablet was 110 per cent (p greater than 0.05), 89 per cent (p greater than 0.05), and 89 per cent (p less than 0.05), respectively, of that from the reference standard-release tablet. The isosorbide dinitrate plasma level data were the more variable, as expected for a drug of low systemic availability subject to extensive first-pass elimination. The posterior probability that the true bioavailability of isosorbide dinitrate was included within the usually accepted limits of 80-120 per cent was 0.74, a value which is probably insufficient to justify claims of bioequivalence with the reference formulation in respect of extent of availability. In contrast, the posterior probability that the bioavailability of the metabolites isosorbide 2- and 5-nitrate was included within these limits was 0.90 and 0.98, respectively. On the basis of the mononitrate data, these two formulations may be judged bioequivalent in respect of extent of availability despite a formal statistically significant formulation-related effect in the analysis of variance of the isosorbide 5-nitrate bioavailability data. Claims of bioequivalence of isosorbide dinitrate sustained-release formulations may be more economically justified by analysis of the mononitrate plasma concentrations, although concentrations of the formulated parent dinitrate should also be known.

Adolescent↗
PubMedDate not supplied

Pharmacokinetics and bioavailability of the anti-emetic agent bromopride.

The pharmacokinetics of bromopride, an anti-emetic agent chemically related to metoclopramide, has been investigated in normal human subjects. After intravenous bolus doses of 10 mg, a one-compartment open model appeared adequate to describe the plasma drug concentration data. The systemic clearance of bromopride was 899 ml min-1 +/- 22 per cent CV, the volume of distribution was 2151 +/- 16 per cent CV, and the elimination half-life was 2.9 h +/- 21 per cent CV. Over a wide drug concentration range of up to 650 ng ml-1, bromopride was only 40 per cent bound to plasma proteins. The systemic availability of orally and intramuscularly administered solution doses of 20 mg of bromopride was 54 per cent and 78 per cent, respectively. Formulation of bromopride as the solid material in capsules delayed absorption but did not affect the extent of drug bioavailability. The pharmacokinetics of bromopride appeared similar to that of metoclopramide. No evidence for non-linear kinetics was found when bromopride was administered orally in the dose range 10-30 mg: after single oral doses of 10, 20, and 30 mg, peak mean plasma drug concentrations were 20 ng ml-1 +/- 32 per cent CV, 38 ng ml-1 +/- 16 per cent CV, and 64 ng ml-1 +/- 23 per cent CV, respectively.

Administration, Oral↗
PubMedDate not supplied

Plasma concentrations and relative bioavailability of naftidrofuryl from different salt forms.

The relative bioavailability of the vasodilator naftidrofuryl from formulations containing its oxalate or citrate salt has been estimated using a specific HPLC assay, and a less specific fluorimetric assay, to measure plasma drug concentrations. The conclusions of the study were the same irrespective of the assay employed. The relative rate, but not the extent, of bioavailability of naftidrofuryl from the citrate salt (peak 1096 ng ml-1 at 0.76 h) was marginally greater (p = 0.003) than that from the oxalate salt (peak 922 ng ml-1 at 0.94 h). The degree of intersubject variability was similar after administration of either salt form. The mean half-life of naftidrofuryl was 1.8 h and its mean residence time was 2.5 h.

Adult↗
PubMedDate not supplied

Plasma concentrations of isosorbide dinitrate after cutaneous and sublingual doses to human subjects.

After application of 100 mg (nominal dose) isosorbide dinitrate as an ointment to the skin of human subjects, mean drug concentrations were 1 to 2 ng/ml for 1.5 hour and reached a peak of 6.2 ng/ml at 6 hours. Thereafter, mean concentrations declined slowly to 2.9 ng/ml at 12 hours and 1.2 ng/ml at 24 hours. After a sublingual dose of 5 mg isosorbide dinitrate, mean drug concentrations reached a peak of 15.9 ng/ml at 0.5 hour and declined with a half-life of about 50 minutes. The mean bioavailability of isosorbide dinitrate from the ointment was estimated as 30 per cent of that from the sublingual tablet when corrected for differences in dose/body weight ratio. The results demonstrate that concentrations of isosorbide dinitrate in plasma can be maintained for relatively long periods when the drug is applied to the skin.

Administration, Topical↗
PubMedDate not supplied

The metabolic fate of 11-bromo[15-3H]vincamine in man.

During 5 days following a single oral dose of 3H-11-bromovincamine (40 mg) to two human subjects, means of 55% and 27% of the 3H dose were excreted in the urine and faeces respectively, mainly within 24 and 48 h. Mean plasma concentrations of 3H reached a peak (1900 ng equiv./ml) at 1 h after dosing and declined biphasically with half-lives of 5 h and 11 h which were similar to half-lives for urinary excretion of 3H. Parent drug and 11-bromovincaminic acid were the major dose-related components in plasma at 1.5 and 3 h. Mean plasma concentrations of 11-bromovincamine reached a peak (620 ng/ml) at 0.75 h and declined biphasically with half-lives of about 1 h and 5 h. The major urinary metabolite was 11-bromovincaminic acid (31% dose). Also present in urine were 11-bromovincamine (3%), 11-bromoapovincamine (1%) and 2 unknown metabolites (9% and 6%). Similar metabolites were detected in faecal extracts. If inadequately stored in biological samples, 11-bromovincamine could be hydrolysed to 11-bromovincaminic acid and be epimerised to 11-bromo-epivincamine.

Adult↗
PubMedDate not supplied

Metabolism of the anti-depressant lortalamine.

Humans excreted an oral dose of 5 mg of the anti-depressant lortalamine (radiolabelled with carbon-14) mainly in the urine (98% during 5 days). Plasma 14C concentrations were highest (about 44 ng equiv./ml) between 1.5-3 h when the corresponding concentrations of unchanged drug were about 17 ng/ml. Unchanged drug concentrations appeared to decline with a half-life of about 5 h. Concentrations of 14C then declined rapidly and were below the limits of detection (12 ng equiv./ml) at 24-36 h. Measurement of whole-blood 14C concentrations showed that there was some uptake into the blood cells (about 65% of the peak plasma 14C level). Radioactivity in the urine was mainly associated with unchanged drug and three metabolites. The major metabolite (about 50% urinary 14C) was identified by mass spectrometry as the N-demethylated compound and another metabolite as a keto derivative of lortalamine where oxidation had occurred in the piperidine ring.

Adult↗
PubMedDate not supplied

Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the rat.

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in rats, and eliminated more slowly by females than by males. The respective half-lives were about 4.9 and 2.1 h. Following single intravenous doses, dexloxiglumide was characterised as a drug having a low clearance (6.01 and about 1.96 ml/min/kg in males and females respectively), a moderate volume of distribution (Vss, 0.98 and about 1.1 L/kg in males and females respectively) and a high systemic availability. It was extensively bound to plasma proteins (97%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. Peak 14C concentrations generally occurred at 1-2 h in males and at 2-4 h in females. Tissue 14C concentrations then declined by severalfold during 24 h although still present in most tissues at 24 h but only in a few tissues (such as the liver and gastrointestinal tract) at 168 h. Decline of 14C was less rapid in the tissues of females than in those of males. Single intravenous or oral doses were mainly excreted in the faeces (87-92%), mostly during 24 h and more slowly from females than from males. Urines contained less than 11% dose. Mean recoveries during 7 days when 14C was not detectable in the carcass except in one female rat ranged between 93-101%. Biliary excretion of 14C was prominent (84-91% dose during 24 h) in the disposition of 14C which was also subjected to facile enterohepatic circulation (74% dose). Metabolite profiles in plasma and selected tissues differed. In the former, unchanged dexloxiglumide was the major component whereas in the latter, a polar component was dominant. Urine, bile and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. up to 63% dose in bile). LC-MS/MS showed that dexloxiglumide was metabolised mainly by hydroxylation in the N-(3-methoxypropyl)pentyl sidechain and by O-demethylation followed by subsequent oxidation of the resulting alcohol to a carboxylic acid.

Absorption↗
PubMedDate not supplied

Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the dog.

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in dogs and also eliminated rapidly with a short half-life. Following single intravenous doses, dexloxiglumide was characterised as a drug having a high clearance (30.7 and 27.0 ml/min/kg in males and females respectively), a low volume of distribution (Vss, 0.34 and 0.27 L/kg in males and females respectively) and a moderate systemic availability (about 33%). It was extensively bound to plasma proteins (89%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the kidney, liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. 14C concentrations generally peaked at 0.25h and declined rapidly during 24h being present only in a few tissues (such as the kidney, liver and gastrointestinal tract) at 24h. Single intravenous or oral doses were mainly excreted in the faeces (77-89%), mostly during 24h. Urine contained up to 7.5% dose. Mean recoveries during 7 days ranged between 93-97%. Biliary excretion of 14C was prominent (64% dose during 24h) in the disposition of 14C which was probably also subjected to some limited enterohepatic circulation. Unchanged dexloxiglumide was the major component in plasma. Urine and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. about 55% dose in faeces). LC-MS/MS of urine and bile extracts showed that dexloxiglumide was metabolised mainly by O-demethylation and by conjugation with glucuronic acid.

Absorption↗
PubMedDate not supplied

Biotransformation of methyl 5-cyclopropylcarbonyl-2-benzimidazolecarbamate (ciclobendazole) in rats and dogs.

A major metabolite of ciclobendazole (methyl 5-cyclopropylcarbonyl-2-benzimidazolecarbamate) excreted in the urine, bile, and feces of rats was methyl 5-cyclopropylcarbonyl-6-hydroxy-benzimidazolecarbamate, established by comparison of the proton magnetic resonance and mass spectra with that of the authentic compound. This compound represented 8.2% and 7.1% of the dose, respectively, in extracts of 24-hr urine and 48-hr feces samples of rats, but was only a minor metabolite in dog urine (1% of the dose). The unchanged drug was only detected in dog feces, the major route of excretion of radioactivity in the dog. 5-Cyclopropylcarbonyl-2-amino-benzimidazole was present in rat urine (2.5% of the dose). A major metabolite in dog bile was probably 5-cyclopropylcarbinol-2-aminobenzimidazole, formed by loss of the methoxycarbonyl group and reduction of the carbonyl function in the 5-position.

Animals↗
PubMedDate not supplied

Determination of amitriptyline and its major basic metabolites in human urine by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the routine, simultaneous determination of amitriptyline and its basic metabolites in human urine has been developed. 10-Hydroxylated metabolites are analyzed as their 10,11-dehydro analogs, and primary and secondary amines as their N-trifluoroacetyl derivatives. The use of gradient elution enables amitryptyline, nortriptyline trifluoroacetate, desmethylnortriptyline trifluoroacetate, and the corresponding 10, 11-dehydro analogs to be separated from both each other and from the internal standard used. In this way all six compounds may be conveniently measured in a single chromatogram, with good sensitivity and accuracy. Following administration of a single oral dose (25 mg) of amitriptyline hydrochloride to two human subjects, no unchanged drug was found in any of the urine samples analyzed up to 72 hr after dosing, and only small amounts of nortriptyline and desmethylnortriptyline were observed. 10-hydroxynortriptyline was the major biotransformation product (about 40% of the dose) in urine, with 10-hydroxyamitriptyline and 10-hydroxydesmethylnortriptyline present as minor metabolites. During 72 hr after administration, approximately 60% of the dose was recovered as these five metabolites.

Adult↗