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Biomedical subjects

S J Warrington

Publications and source records attributed to S J Warrington.

At least 19 recordsLinked to original sources
PubMed1997

Pharmacokinetics of isosorbide dinitrate in healthy volunteers after 24-hour intravenous infusion.

No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate (IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2 micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady-state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half-lives of ISDN, IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38 minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min-1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.

Adult↗
PubMed1996

The time course of binding to striatal dopamine D2 receptors by the neuroleptic ziprasidone (CP-88,059-01) determined by positron emission tomography.

Positron emission tomography (PET) and 11C-raclopride were used to assess the time course of binding to central dopamine D2 receptors by the novel neuroleptic ziprasidone. In a third party blind study, six healthy male control subjects received a predose of 40 mg ziprasidone and were scanned at an interval of between 4 and 36 h post-dose. One additional subject was assigned to placebo predose and was scanned at 4 h post-dose. Binding potential (BP) was compared with that seen in the subject predosed with placebo and with that seen in nine unmedicated normal volunteers. Subjects studied up to 12 h post-dose had BPs that were greater than 2 SD less than the mean BP, indicative of extensive D2 receptor binding by ziprasidone. With increasing time between dosing and PET scanning there was a curvilinear increase in BP, so that all studies performed at or after 18 h post-dose gave BPs in the normal range (mean +/- 2 SD). Elevated prolactin levels returned to within the normal range by 18 h post-dose. PET measures of binding potential correlated significantly with serum levels of ziprasidone at the time of scanning and less significantly with absolute prolactin levels at the same time.

Adult↗
PubMed1995

Hemodynamic and humoral effects at rest and after head-up tilt tests during 24-hour infusion of a new nitrate ester, ITF 296, compared with ISDN and placebo in healthy volunteers: a double-blind, randomized, within-subject study.

A double-blind, randomized, three-way complete crossover study was carried out to compare pharmacodynamic effects and tolerability during a 24-h intravenous infusion of ITF 296, isosorbide dinitrate (ISDN), and placebo, in the supine position and during 70 degrees head-up tilt. Ten healthy men aged 21-34 years participated in the study to obtain complete data in nine. Dosing started at 1 microgram/kg/min and was titrated up during the first 30 min of infusion, to produce a 10% reduction in diastolic blood pressure (DBP). At least 6 days elapsed between consecutive treatments. Heart rate (HR) and blood pressure were measured at least half hourly throughout the infusion period and up to 2 h afterwards. Systolic time intervals were measured before and at 0.5, 1, 2, 3, and 24 h of infusion in the fasting state. Tilt tests (70 degrees head-up for 2 min) were performed at 1, 6, 12, and 24 h of infusion. From 60 min before tilt, during tilt, and up to 15 min after end of tilt, ECG was monitored and BP, HR, and b/a ratio were recorded by means of fingertip plethysmography. Plasma-renin activity and concentrations of epinephrine and norepinephrine were measured preinfusion, and before and after tilt tests. Subjects were questioned frequently about adverse events. General tolerability of ISDN in the nine subjects who completed the study was poor, with eight suffering from headache and four from symptoms suggesting postural hypotension during tilt tests. Tolerability of ITF 296 was better, with 5 of 10 subjects reporting headache and 2 of 10 symptoms of postural hypotension during the first tilt only. Both active treatments successfully reduced DBP by at least 10% in all subjects at similar dose levels (final infusion rates 2.8 and 2.3 micrograms/kg/min for ITF 296 and ISDN, respectively). Systolic blood pressure (SBP) was reduced by about 6-7 mm Hg by both treatments. HR was increased by about 5 beats/min by ISDN but not by ITF 296. Those changes in BP and HR persisted throughout the 24-h infusion and reversed when it was discontinued. Fingertip plethysmography showed a profound reduction of b/a ratio, which persisted throughout the 24-h infusion. ISDN had consistently greater effects than ITF 296, suggesting that ISDN has the greater effects on small arterial vessels. Both active treatments reduced QS2 index throughout the 24-h period. Both treatments also reduced left-ventricular ejection time (LVET) index up to 3 h of infusion, with ISDN having the greater effects on LVET index and ITF 296 being intermediate between ISDN and placebo. ISDN prolonged pre-ejection period (PEP) at 1 h, had no effect at 2 h, and shortened PEP at 3 and 24 h. ITF 296 decreased PEP consistently during the 24-h infusion. Plasma-renin activity, epinephrine, and norepinephrine were increased by ISDN substantially more than by ITF 296. These results show that both ITF 296 and ISDN had comparable effects on diastolic blood pressure at similar dose-levels. ISDN increased HR, whereas ITF 296 did not. b/a Ratio was reduced more by ISDN, suggesting a greater activity on small arterial vessels. Arterial effects were maintained throughout the 24-h infusion. ISDN had a greater effect on venous return than ITF 296. ITF 296 seemed to show more balanced effects on preload and afterload than ISDN. ISDN caused significantly greater neurohumoral counter-regulation than ITF 296. Hemodynamic response to tilt was attenuated, as judged by the fact that hypotension occurred only during the early hours of the infusion, but the variability in the response of BP to tilt does not allow any firm conclusions to be drawn about possible development of tolerance. Tolerability of ISDN was poor and that of ITF 296 was better.

Adult↗
PubMed1994

Interrelationships between Helicobacter pylori infection, nonsteroidal antiinflammatory drugs and gastroduodenal disease. A prospective study in healthy volunteers.

Helicobacter pylori and nonsteroidal antiinflammatory drugs independently cause gastroduodenal mucosal injury but the relationship between them remains unclear. We have performed a double-blind, parallel-group, placebo-controlled prospective study in 77 healthy volunteers aged 19-35 years who were randomly allocated to indomethacin (N = 15), one of three oxicams (piroxicam, chlortenoxicam, or CHF 1194; N = 36), or placebo (N = 26). Esophagogastroduodenoscopy was performed before and after four weeks of treatment and the mucosal appearances graded. Colonization with H. pylori was established at each endoscopy and gastrointestinal symptoms were assessed by daily diary card. Seven subjects (9%) were positive for H. pylori before treatment (one placebo, one indomethacin, and five an oxicam); their H. pylori status remained unchanged. Two of 70 H. pylori-negative subjects became H. pylori-positive (2.9%), both of whom had received placebo. The endoscopic score deteriorated in 1/6 drug-treated H. pylori-positive subjects and in 0/1 taking placebo. Of the H. pylori-negative subjects whose endoscopic score deteriorated, three (13%) were taking placebo, four (28.6%) indomethacin, and eight (25.8%) an oxicam. Upper gastrointestinal symptoms were reported in eight (30.8%) of the subjects taking placebo (one subject negative for H. pylori became positive), eight (53.3%) indomethacin (one H. pylori-positive), and 10 (27.8%) an oxicam (one H. pylori-positive). There were no statistically significant differences between the H. pylori-negative and H. pylori-positive groups whether on drug or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and 11C-raclopride.

Positron emission tomography (PET) and 11C-raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of 11C-raclopride decreased in a dose dependent manner, and 85% dopamine D2 receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study high-lights the potential of positron emission tomography in the preclinical evaluation of new drugs.

Adult↗
PubMed1993

Renal and general tolerability of repeated doses of nimesulide in normal subjects.

The renal and general tolerability of nimesulide was studied in 16 healthy men, randomised to 4 groups of 4 subjects. The groups all underwent 2 treatment periods of 7 days each, separated by a washout period of 14 days. The second treatment period was always at a higher dosage level than the first. There were 4 dosage regimens: placebo, and nimesulide 200, 300 and 400mg, all given twice daily by mouth according to a double-blind design. The tolerability of nimesulide was assessed by regular clinical examination, nondirected questions about adverse events, haematological and biochemical screening, and daily urine testing. Plasma and urinary concentrations of Tamm-Horsfall glycoprotein (THG), urinary retinol-binding protein (RBP) and beta-N-acetyl glucosaminidase (NAG) on days 1, 3, 7, and 10 of each period were used as selective indicators of nephrotoxicity. The highest dose of nimesulide (800mg daily) was associated with abdominal pain and indigestion in 5 of 8 recipients. The 400 and 600mg daily dosages were well tolerated. There were no clinically significant alterations in the haematological or biochemical screening tests during the study, and daily urinalysis remained normal throughout. The renal toxicity tests showed no evidence of nephrotoxicity associated with the administration of nimesulide in 14 subjects. The other 2 subjects each had modest increases in either urinary THG or NAG concentrations during treatment with nimesulide 800mg daily, but the results of their other tests remained normal. The study, therefore, showed only equivocal evidence of minor renal toxicity with nimesulide 800mg daily. Nimesulide 400 and 600mg daily were well tolerated in all respects, even though these dosages are higher than those recommended for clinical use.

Adult↗
PubMed1992

Clinical implications of the pharmacology of serotonin reuptake inhibitors.

The selective serotonin reuptake inhibitors (SSRIs) are a tribute to the ingenuity of pharmacologists and designers of molecules. Not only do these drugs have remarkable selectivity for the reuptake of serotonin compared with other monoamines, but also they have a commendable lack of affinity for receptors including the serotonin receptor. In contrast, the classical tricyclic antidepressants (TCAs) are less specific in their pharmacological action. In addition to inhibiting the reuptake of serotonin, TCAs inhibit the uptake of noradrenaline, dopamine and tyramine, and antagonize cholinergic (muscarinic), adrenergic and histaminergic receptors. Moreover, TCAs have quinidine-like anti-arrhythmic activity and lower the seizure threshold. Clinical investigations have shown that the SSRIs have equivalent therapeutic efficacy compared with the TCAs in the treatment of depression. However, the pharmacological specificity of the SSRIs is a clinical advantage since they lack the propensity to cause dry mouth, blurred vision, urinary hesitancy, constipation, hypotension and arrhythmia. Furthermore, the SSRIs are relatively safe in overdosage. The similarities between the SSRIs are more obvious than their differences: all are highly potent and selective inhibitors of serotonin reuptake with efficacy in the treatment of depression. Nevertheless, each has a distinctive pharmacological profile. In this review the characteristics desired in an "ideal" antidepressant are examined, and the ways in which the TCAs and SSRIs fit this ideal are compared.

Antidepressive Agents, Tricyclic↗
PubMed1992

Cardiovascular effects of antidepressants: studies of paroxetine in healthy men and depressed patients.

The classical tricyclic antidepressant drugs effectively relieve the symptoms of depression, but they have the potential to be severely toxic to the cardiovascular system--including postural hypotension after therapeutic doses and lethal arrhythmias after overdosage. Paroxetine has been shown to be of similar efficacy to the tricyclic antidepressants but has lower cardiovascular toxicity in animal models and has no effects on heart rate, blood pressure or the electrocardiogram in healthy men receiving single 20-40 mg doses. The results of two contrasting studies in depressive patients and healthy men provide strong evidence that therapeutic doses of paroxetine lack any important haemodynamic or electrophysiological effects.

Blood Pressure↗
PubMed1991

Clinical implications of the pharmacology of sertraline.

Sertraline is slowly absorbed after oral administration, with peak plasma concentrations at 6-8 h. Plasma concentrations are linearly related to dose. The elimination half-life is about 32 h; metabolism is by demethylation to an inactive metabolite. Once-daily dosing is recommended, with steady state being reached after about 7 days. The kinetics of sertraline in the elderly and in patients with renal impairment are similar to those in young healthy female volunteers. In young male volunteers, peak plasma concentrations were lower, and elimination half-life shorter, than in elderly men or both groups of women. Nevertheless, no reduction in dosage is recommended for these groups. Sertraline is highly active in animal models of depression, and administration of the drug to healthy human beings causes a selective, dose-related inhibition of 5-hydroxytryptamine (5-HT) uptake into blood platelets. Single doses of sertraline in volunteers caused changes in the quantitative pharmaco-electroencephalogram suggesting antidepressant and anxiolytic actions, with sedative potential evident only at doses of 200 mg or more. Sertraline does not impair psychomotor performance, including simulated car driving, and overall seems neither stimulating nor sedating: an increase in critical flicker fusion threshold suggests a slight alerting effect, whereas subjective tests indicate an increase in perceived sedation at doses of 100 mg or more. No potentiation of the effects of ethanol has been noted in either young or elderly subjects. No adverse effects on the electrocardiogram, blood pressure, or systolic time intervals have been detected, and sertraline lacks anticholinergic action. These studies imply a low probability of adverse central nervous and cardiovascular effects. Sertraline is probably a weak inducer of hepatic microsomal enzyme activity. Sertraline does not affect the clearance of lithium but there may be a pharmacodynamic interaction which leads to increased tremor when the drugs are given together. No clinically relevant effects were noted in the interaction studies with digoxin, atenolol and diazepam. The pharmacokinetics and pharmacodynamics of sertraline are generally favourable. However, caution is needed when sertraline is given to patients receiving lithium or drugs with a low therapeutic ratio, such as corticosteroids, oral hypoglycaemic agents, and warfarin.

1-Naphthylamine↗
PubMed1991

Ethics of evaluation of new drugs in human volunteers.

Experiments in human volunteers are a vital part of the evaluation of most new drugs. Are such experiments ethical? This question is discussed in the light of four ethical principles: justice, beneficence, non-maleficence and respect for autonomy. Problem areas include recruitment of volunteers, obtaining consent, payment for participation and special groups such as students and staff of research institutions, the poor, women of child-bearing potential, children and elderly volunteers. Drug evaluation in volunteers does present ethical difficulties, but none of these is insurmountable.

Beneficence↗
PubMed1991

A pharmacokinetic and dynamic study of single nightly doses of conventional and controlled release formulations of trazodone.

We studied the pharmacokinetics and dynamics of single evening oral doses of conventional capsules (100 mg) and a controlled release formulation (150 mg) of trazodone in 12 fasting and non-fasting young healthy volunteers. When corrected for the different doses used, there was no significant difference among the areas under the plasma concentration-time curves (AUC) for the conventional capsules and the controlled release tablets under fasting and non-fasting conditions. Both conventional and controlled release formulations were followed by a reduction in critical flicker fusion threshold (CFFT) and this effect was not influenced by the administration of food before dosing. After both conventional and controlled release formulations, blood pressure was significantly lower when medication had been given in the fasting state than when it had been given after food. The frequency of adverse symptoms was greater after the controlled release (150 mg) than after the conventional (100 mg) formulation. We conclude that there is no obvious advantage to the controlled release formulation (150 mg) and that conventional trazodone (100 mg) should be taken after food when it is given at night.

Adult↗
PubMed1990

Betaxolol and glucose-insulin relationships: studies in normal subjects taking glibenclamide or metformin.

1. The potential interaction between selective beta 1-adrenoceptor blockers and sulphonylureas or biguanides was studied by comparing the beta 1-adrenoceptor antagonist betaxolol with placebo in 12 normal subjects taking glibenclamide or metformin in a single-blind crossover group study. 2. After a 4 day run-in period on no treatment, six subjects took glibenclamide 2.5 mg twice daily, and six subjects took metformin 850 mg twice daily from day 5 to day 19. All subjects took betaxolol 20 mg daily from day 10 to day 13, and placebo from day 5 to day 10 and from day 13 to day 19. 3. Plasma glucose and insulin concentrations were measured fasting and 60 min after a standard breakfast for 3 successive days during each study treatment; plasma potassium, sodium and betaxolol concentrations were also measured. 4. Fasting glucose, insulin and potassium concentrations did not differ significantly between betaxolol and placebo treatment periods in either glibenclamide- or metformin-treated groups. Post-prandial glucose and insulin concentrations were lower and higher, respectively, relative to fasting concentrations but there was no significant difference between any of the treatment periods. Glibenclamide produced significant increases in insulin concentrations compared with drug-free periods (P less than 0.01). Plasma potassium and sodium concentrations were not affected by any of the treatments. 5. Plasma betaxolol concentrations were adequate for beta 1-adrenoceptor blockade. 6. This study suggests that selective beta 1-adrenoceptor blockade with betaxolol does not change fasting or post-prandial glucose-insulin relationships during simultaneous treatment with either the sulphonylurea glibenclamide or the biguanide metformin.

Adult↗
PubMed1990

Lornoxicam, indomethacin and placebo: comparison of effects on faecal blood loss and upper gastrointestinal endoscopic appearances in healthy men.

Forty-five healthy men aged 21-34 years took part in a double-blind, parallel-group, placebo-controlled study of the effects of 28 days' treatment with lornoxicam 4 mg twice daily or indomethacin 50 mg twice daily on faecal blood loss and the endoscopic appearances of gastric and duodenal mucosa. After an initial endoscopic examination, subjects received, intravenously, on day 0, autologous erythrocytes labelled with 51Cr. Complete daily faecal collections were then made from days 6-12, 20-26 and 34-40. The drug treatments or placebo were given from days 13-41. Faecal blood loss was calculated from 51Cr-specific activity of blood and faeces. Endoscopy was repeated 4-8 hours after the last dose of medication; mucosal appearance was graded on a 5-point scale. Lornoxicam caused no more adverse events than placebo; indomethacin caused more indigestion and central nervous system effects, and one subject in this group was withdrawn from the study. Median total blood losses during the pre-treatment and the second and fourth weeks of treatment were respectively 3.33, 3.95 and 5.71 ml for lornoxicam, 2.87, 7.04 and 7.75 ml for indomethacin, and 4.55, 3.64 and 4.13 ml for placebo. Differences between treatments were not statistically significant (P = 0.081 for second week of treatment, P = 0.383 for fourth week of treatment; Kruskal-Wallis test). The effect of chlortenoxicam on faecal blood loss in this study was thus intermediate between placebo and indomethacin, but within- and between-subject variability was such that the differences were not statistically significant. Endoscopic findings were normal in most subjects before and after all treatments, but indomethacin was associated with a slightly greater deterioration in endoscopic score and was the only treatment associated with Grade 3 appearance (in a single patient) in post-treatment endoscopy.

Adult↗
PubMed1990

Bisoprolol: studies of potential interactions with theophylline and warfarin in healthy volunteers.

Many patients receiving bisoprolol treatment might also require warfarin or theophylline therapy. Two studies were carried out in healthy volunteers to investigate the possibility that bisoprolol might interact with warfarin or theophylline, both of which have low therapeutic ratios. In a balanced, two-way, crossover study, eight men and four women took bisoprolol 10 mg daily for 14 days. They were divided into two groups of six volunteers. On the tenth day of treatment, six subjects received theophylline 375 mg (Nuelin tablets) by mouth and the pharmacokinetics of theophylline were determined. After a washout period of 7 days, they also underwent determination of single-dose theophylline kinetics. The other six subjects had single-dose theophylline kinetics determined 7 days before the first dose of bisoprolol, and then again after 10 days of bisoprolol treatment. Concurrent administration of bisoprolol did not influence the tolerability of theophylline and had no significant effect on any of the pharmacokinetic parameters for theophylline. In a separate study, 12 healthy men received warfarin daily until their prothrombin times were about 1.5 x control. They then received bisoprolol 10 mg daily p.o. for 10 days; warfarin was continued until 5 days after the end of bisoprolol treatment. Bisoprolol and warfarin treatments were well tolerated, and there was no effect on prothrombin times of either starting or stopping bisoprolol treatment. These studies show no effect of bisoprolol treatment upon theophylline pharmacokinetics, and no evidence of an effect of bisoprolol upon low-level anticoagulation with warfarin. Nevertheless, care should always be taken when changes are made in the medication of patients receiving theophylline or warfarin.

Adrenergic beta-Antagonists↗
PubMed1990

Renal and gastrointestinal tolerability of lornoxicam, and effects on haemostasis and hepatic microsomal oxidation.

Three separate studies were carried out to assess the renal and gastrointestinal tolerability of lornoxicam, and its effects on haemostasis and hepatic microsomal oxidation. Haemostasis and hepatic microsomal oxidation. Six men and 6 women had salivary antipyrine half-life determined before and on the last day of 14 days' treatment with lornoxicam 4 mg twice daily. Haemostasis, coagulation and thrombolysis were assessed ex vivo using a haemostatometer before and on Day 14 of lornoxicam treatment. Lornoxicam 4 mg twice daily for 14 days had no significant influence on antipyrine elimination half-life or haemostasis, coagulation and thrombolysis. Renal tolerability. Three groups of 8 healthy young men received respectively 4, 6 and 8 mg lornoxicam twice daily by mouth for 22 days. Nephrotoxicity studies on serum and urine were done repeatedly before, during and after lornoxicam treatment. Serum and urine creatinine, serum Tamm-Horsfall glycoprotein (THG), and urine n-acetylglucosaminidase (NAG), THG and retinol binding protein (RBP) concentrations showed sporadic values outside the laboratory reference range, but these were not in any subject temporally related to drug treatment and were unrelated to dose. Urine microscopy was unremarkable. Thus this study yielded no evidence that lornoxicam has any nephrotoxic effects in healthy young men receiving doses up to 8 mg twice daily for 22 days. Gastrointestinal blood loss and endoscopy. The gastrointestinal effects of lornoxicam 4 mg, indomethacin 50 mg or placebo twice daily for 29 days were evaluated in 45 healthy men. After an initial endoscopic examination, subjects underwent 51Cr red cell labelling. Complete daily faecal collections were then made from Days 6-12, 20-26 and 34-40. Treatments were given from Days 13-41. Endoscopy was repeated 4-8 h after the last dose of medication. Faecal blood loss during lornoxicam treatment was greater than placebo and less than indomethacin, but within- and between-subject variability was such that the differences were not statistically significant. Endoscopic findings were normal in most subjects before and after all 3 treatments.

Adult↗
PubMed1990

Effects of single doses of a 20 mg frusemide/2.5 mg amiloride combination, 20 mg frusemide and placebo on plasma and urine electrolytes in healthy men.

The effects of single doses of a combination of 20 mg frusemide and 2.5 mg amiloride, of 20 mg frusemide and of placebo on plasma and urinary electrolytes were assessed in healthy volunteers using a randomized, crossover study. The combination significantly (P less than 0.001) increased the urinary volume compared with frusemide alone or placebo. Mean total urinary sodium was also significantly (P less than 0.001) increased by frusemide/amiloride compared with both frusemide and placebo. Mean total potassium excretion was reduced significantly (P less than 0.01) by frusemide/amiloride but total magnesium excretion was not significantly affected. The effects of frusemide/amiloride on plasma sodium, magnesium and potassium were similar to those of placebo. It is concluded that frusemide/amiloride has a greater diuretic and natriuretic effect than frusemide alone and does not increase potassium loss.

Adult↗
PubMed1989

High-performance liquid chromatographic method for the radiometric determination of [14C] bucromarone in human plasma utilizing non-radiolabeled bucromarone as an internal standard.

A novel radiometric high-performance liquid chromatographic (HPLC) method was developed for the determination of [14C]bucromarone in human plasma. The procedure involved the addition of non-radiolabeled bucromarone hydrochloride to each plasma sample as an internal standard; the plasma sample was then extracted, and the bucromarone was separated from its metabolites and endogenous compounds by reversed phase HPLC. The concentration of [14C]bucromarone in each plasma sample was calculated from the ratio of the amount of radioactivity in the eluate fraction corresponding to bucromarone and the peak height of the ultraviolet absorbance (210 nm) of the non-radiolabeled bucromarone used as an internal standard. The lower limit of quantitation for bucromarone free base in this assay was 8 ng/ml when [14C]bucromarone succinate had a specific activity of 0.5 microCi/mg. The coefficients of variation for the experimentally determined concentrations of bucromarone in spiked plasma samples were 6.8 and 14.3% at concentrations of 80 and 20 ng/ml, respectively. This method was used to determine concentrations of bucromarone in the plasma of healthy volunteers who were given intravenous infusions of [14C]bucromarone succinate. In general, the methodology should be applicable to any radiolabeled compound that possesses appreciable ultraviolet absorbance.

Anti-Arrhythmia Agents↗