Pharmacokinetics and metabolism of the anti-oestrogen droloxifene in female human subjects.

1. Single oral doses of a solution formulation of (14)C-droloxifene citrate (141 mg) appeared to be rapidly and well absorbed in four post-menopausal female subjects. Peak plasma concentrations (C(max)) of total (14)C (1260 ng eq. ml(-1)), droloxifene (196 ng ml(-1)) and the major metabolite droloxifene glucuronide (851 ng eq. ml(-1)) occurred at 0.9-1.1 h (T(max)) and declined bi-exponentially with terminal half-lives of 45.0, 31.6 and 32.0 h respectively. The mean AUCs of droloxifene and the major metabolite were 21 and 37% respectively that of total (14)C. 2. Total (14)C was excreted slowly, mainly in the faeces. Mean totals of 6.6 and 90.3% of the dose were excreted in the urine and faeces respectively during 11 days. The data were consistent with biliary excretion and enterohepatic circulation of the major metabolite, droloxifene glucuronide. 3. GC-MS showed that the major (14)C-components in 0-24-h urine were droloxifene (mean 0.4% dose) and its glucuronide (2.3% dose), and in faeces were droloxifene (60.2% dose) and N- desmethyldroloxifene (4.2% dose). Other components in faeces corresponded chromatographically to reference standards, droloxifene N-oxide (1.9% dose), side-chain hydroxylated droloxifene (dimethylamine moiety of droloxifene side-chain replaced by hydroxyl, 1.3% dose) and droloxifene glucuronide (10.7% dose). The latter was resistant to enzymic hydrolysis by the beta-glucuronidase used. 4. Intersubject variability in the pharmacokinetics of droloxifene in this study was relatively low (CV < 20% for AUC and half-life).

Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects.

The pharmacokinetics of the anti-inflammatory drug benzydamine were determined after intravenous infusion of 5 mg to six healthy male subjects. Benzydamine was characterized as a drug of relatively low systemic clearance (ca. 160 ml min-1) but high volume of distribution (ca. 1101); the apparent terminal half-life in plasma was ca. 8 h. Benzydamine was well absorbed after oral administration, as indicated by a mean systemic availability of 87 per cent. However, absorption of the drug was low (less than 10 per cent of the dose) after its use by male subjects as a mouthwash, or after its application to female subjects as dermal cream and vaginal douche preparations. The data suggest that benzydamine is generally not well absorbed through the skin and non-specialized mucosae, thereby limiting unrequired systemic exposure to this drug when it is used by these routes.

Dose-proportional pharmacokinetics of cefepime in rats.

Cefepime (BMY-28142) is a new parenteral cephalosporin antibiotic with excellent activity against a broad-spectrum of clinically important pathogens resistant to other new cephalosporins. A single bolus dose of 10, 20 or 40 mg/kg cefepime was given i.v. to male and female Sprague-Dawley rats from which blood and urine samples were collected. For statistical reasons, pharmacokinetic parameters (AUC, Kel) were derived by fitting an exponential curve to the plasma concentrations; subsequently, contrasts were made between the different doses for AUC and Kel and, in addition, plasma concentrations observed after the first sampling time (Cmax). Cmax and AUC appeared to be linearly related to the administered dose in both males and females. The dose increased in the ratio 1:2:4 and mean Cmax in male and female rats increased in the ratio 1:2.3:4.1 and 1:2.3:4.4 respectively; similarly, AUC increased in the ratio 1:2.2:4.3 and 1:2.0:4.2 respectively. Deviations from linearity and proportionality were not significant (P0.05). The systemic clearance of cefepime in rats was 2.3 ml/min. The volume of distribution was about 60 ml and cefepime appears to be selectively distributed into the extracellular water. Plasma concentrations declined monoexponentially with a mean half-life of 15-20 min which did not significantly change with increasing doses. The renal clearance of cefepime was 1.8 ml/min and approximately 80% of the dose was excreted in the urine unchanged; renal excretion of cefepime is the major route of elimination in rats. The elimination and distribution characteristics of cefepime in rats were similar to those observed in man.

Determination of ximoprofen and its metabolites in human urine by high-performance liquid chromatography with ultraviolet absorbance detection.

A simple, sensitive and selective method for the determination of ximoprofen and its keto and hydroxy metabolites in human urine has been developed using high-performance liquid chromatography in the reversed-phase mode. The limit of reliable determination of ximoprofen and each of its metabolites in urine is about 1 microgram/ml (4 nmol/ml). The method has been applied to urine samples obtained from human volunteers after administration of single intravenous doses of 30 mg of ximoprofen and about 70% dose was accounted for in terms of these compounds and their glucuronic acid conjugates.

Determination of benzydamine and its N-oxide in biological fluids by high-performance liquid chromatography.

A simple, sensitive and selective method for the determination of benzydamine in human plasma and urine, and for benzydamine N-oxide in urine, has been developed using high-performance liquid chromatography in the reversed-phase mode. The limit of reliable determination of benzydamine in plasma was 0.5 ng/ml and that in urine 1 ng/ml; the limit of reliable determination of benzydamine N-oxide in urine was 50 ng/ml. The method has been successfully applied to the analysis of these compounds in biological fluids after administration of intravenous and oral doses of benzydamine to human volunteers.

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.

Pharmacokinetics and metabolism of 14C-tinidazole in humans.

Following intravenous infusion of 800 mg of 14C-tinidazole during 30 min to two human subjects, a mean of 44% of the dose was excreted in urine during the first 24 h, increasing to 63% of the dose during five days: 12% of the dose was excreted in the faeces, indicating the possible involvement of biliary excretion and other secretory processes in the disposition of tinidazole. At 6 min after the end of the infusion, the mean plasma tinidazole concentration was 12 mg/l. Tinidazole was a major component in 0-120 h urine (about 32% of urinary 14C): the major metabolite in the 0-12 h urine examined was ethyl 2-(5-hydroxy-2-methyl-4-nitro-1-imidazolyl)ethyl sulphone (about 30% urinary 14C), the product of hydroxylation and nitro-group migration. These compounds were also present in the faeces. A minor urinary metabolite was 2-hydroxymethyltinidazole (about 9% urinary 14C), which was also present in plasma. The mean pharmacokinetic parameters obtained for tinidazole were similar to those reported in the literature; total clearance 51 ml/min, renal clearance 10 ml/min, volume of distribution 501 and half-life 11.6 h.

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.

Determination of bromopride in human plasma and urine by high-performance liquid chromatography.

Bromopride was measured in plasma and urine using reversed-phase high-performance liquid chromatography employing ultraviolet absorption detection. The limit of detection in plasma was 2 ng/ml, sufficient for pharmacokinetic studies of the drug. Plasma concentrations of bromopride reached mean peak levels (55 ng/ml) at 1 h after single oral doses of 20 mg and declined with a half-life of 4.9 h. Less than a mean of 10% of an oral dose was excreted unchanged in the urine. The assay could also be used to measure metoclopramide in these bio-fluids.

The influence of food and repeated dosing on the bioavailability of indomethacin from a multiple-units controlled-release formulation.

A concomitant meal did not affect the extent of bioavailability of indomethacin from a multiple-units controlled-release capsule formulation containing enteric-coated pellets, but the presence of food delayed absorption. When a capsule containing 75 mg indomethacin was administered after a 12 h fast, the mean peak drug concentrations in plasma of 2.7 micrograms/ml +/- 0.8 SD occurred at a mean time of 4.2 h (range 2-6 h). When this dose was administered with a substantial breakfast, the mean of the peak plasma concentration of 2.2 micrograms/ml +/- 1.0 SD occurred at 6.4 h (range 5-12 h). Secondary peak plasma drug concentrations, occurring at approximately 14 h after dosing, were more prominent and the times to reach the second peak more variable when the capsules were administered with food. Drug bioavailability after co-administration with food was 91% of that following administration after fasting. When the controlled-release capsule was administered during 3 days in a b.i.d. dosage regimen, drug bioavailability was 103% of that from a standard capsule administered q.i.d. The mean peak level after administration of the last dose of 50 mg as controlled-release capsules was 2.5 micrograms/ml +/- 1.1 SD and the means of peak levels after the penultimate and last doses of 25 mg as standard capsules were 2.0 micrograms/ml +/- 0.3 SD and 2.1 micrograms/ml +/- 0.7 SD, respectively. The controlled-release capsule formulation was a reliable and reproducible source of indomethacin when administered as repeated doses or with food.

Determination of heptaminol in human plasma and urine by high-performance liquid chromatography.

Heptaminol was measured in plasma and urine following pre-column derivatisation with o-phthalaldehyde and reversed-phase high-performance liquid chromatography employing fluorescence detection. The limits of detection were sufficient for pharmacokinetic studies of the drug after clinically-used doses. Plasma concentrations of heptaminol reached peak levels (2.19 micrograms/ml) at 0.75 h after single oral doses (0.47 g of heptaminol) and declined with a half-life of 2.1 h (+/- 0.5 S.D.). Heptaminol was well absorbed and excreted rapidly, mainly unchanged in urine, 82% dose (+/- 10 S.D.).

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.

A novel conjugate as a major metabolite of bromperidol in man.

The major urine metabolites of the neuroleptic drug, bromperidol, after oral doses to rats and dogs are p-fluorophenylacetic acid and its glycine conjugate resulting from oxidative N-dealkylation. While the same metabolites were also detected in human urine, also present was a major unknown component representing 50% of the total urine metabolites, which apparently was not formed by rats and dogs to any extent. Mass spectroscopic investigations a substituent attached to the tertiary hydroxyl group. The mass spectrum of the metabolite after trifluoroacetylation was consistent with an O-glucofuranosiduronolactone conjugate of bromperidol.

Bioavailability of indomethacin from two multiple-units controlled-release formulations.

Two multiple-units controlled-release indomethacin capsule formulations containing enteric-coated pellets were bioequivalent to a standard capsule formulation (taken as the reference) in respect of extent of bioavailability in a crossover study with normal human subjects. However, drug absorption from the enteric-coated pellet formulations was slower, when compared to that from the standard reference capsule. The standard reference capsule released 85% of its drug content in vitro during 10 min at pH 6.5 and 98% during 1 h at pH 7.5. On enteric-coated pellet capsule formulation (I) released 77% during 1 h at pH 6.5 and the other (II) released 10% during 1 h at pH 6.5. Release of drug from each capsule of enteric-coated pellets was complete during 1 h at pH 7.5. Although differences in areas under the plasma indomethacin concentration-time curves were not significantly different, the peak plasma levels and the times of their occurrence indicated that the absorption rates of indomethacin decreased in the order, reference formulation greater than pellet formulation I greater than pellet formulation II, which was the same rank order as that of their dissolution rates in vitro. The data indicated that multiple units controlled-release formulations represent a reliable and reproducible source of indomethacin, which by avoiding extremes of local or systemic drug concentrations also should be better tolerated by individuals susceptible to unwanted gastrointestinal and centrally-mediate side-effects.

The metabolic fate of 3[H]econazole in man.

1. Following single oral doses of 3[H]econazole base (500 mg) to two human subjects, excretion of radioactivity was prolonged, and incomplete after five days (means of 40% and 27% dose in urine and faeces respectively). 2. Plasma concn. of unchanged econazole and total radioactivity attained peak values at approx. the same for each subject (1.5 - 3h), but the former declined much faster than the latter. Most of the 3H in early plasma samples was present as unchanged drug and extractable metabolites, but after 24h concn. of econazole were close to the limit of detection (0.04 ug/ml) and very little plasma 3H was extractable, whereas total 3H concn. were still measurable after five days (mean 1.54 ug/ml). Thus, plasma contained metabolites with much longer half-lives than econazole. 3. The main route of biotransformation of econazole in man involved multiple oxidation of the imidazole ring carbons followed by O-dealkylation and conjugation of the resulting alcohols, probably with glucuronic acid.