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Biomedical subjects

A Darragh

Publications and source records attributed to A Darragh.

100 records · Page 6Linked to original sources
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 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

Metabolic fate of the beta-blocker 14C-bupranolol in humans, dogs, and rhesus monkeys.

An oral dose of 14C-bupranolol hydrochloride was well absorbed by humans (100 mg), dogs (1 mg/kg), and rhesus monkeys (1 mg/kg). These species excreted 87.8 and 3.5%, 81.1 and 13.6%, and 92.9 ad 5.0% of the 14C-dose in urine and feces, respectively, mainly in 12 or 24 hr. Mean plasma levels of 14C, which appeared to be almost entirely associated with a single metabolite, peaked at 1 hr in humans (1.6 micrograms-equiv./ml) and dogs (1.6 micrograms-/ml) and at 2 hr in monkeys (0.8 micrograms-equiv./ml). Concentrations initially declined with similar half-lives (about 1.5 hr) in all three species. Biliary excretion of 14C occurred in the animal species in which also peak plasma 14C levels exceeded those in most tissues. Unchanged bupranolol was not detected in plasma; the peak plasma and urinary 14C was mainly associated (greater than 90% in humans) with a metabolite produced by oxidation of the aromatic ring methyl group of bupranolol to a carboxyl group.

Absorption↗