Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects.

The absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan was investigated in healthy male subjects by administration of 14C-labeled compound. Four subjects received a single oral dose of 500 mg of bosentan (3.7 MBq), and four other subjects received a single i.v. dose of 250 mg of bosentan (3.7 MBq). Radioactivity and concentrations of bosentan and its metabolites were measured in plasma, urine, and feces samples. More than 97% of drug-related material was recovered on average within 3.5 days after oral dosing and within 5 days after i.v. dosing. More than 90% of radioactivity was found in feces after both oral and i.v. dosing. Most of the radioactivity in urine and feces represented bosentan and three metabolites. Ro 48-5033, the major metabolite in plasma, urine, and feces, is the result of hydroxylation at the t-butyl group of bosentan. The two other metabolites Ro 47-8634 and Ro 64-1056 represent minor metabolite species. Ro 47-8634 is the product of O-demethylation of the phenolic methyl ester, and Ro 64-1056 is generated by both demethylation and hydroxylation. The radioactivity in plasma could almost entirely be attributed to bosentan and the two metabolites Ro 48-5033 and Ro 47-8634, whereby both metabolites exhibited much lower plasma levels than bosentan. Hepatic metabolism followed by biliary excretion of the metabolites apparently represents the major pathway of elimination for bosentan in humans.     

Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys

DJ-927, currently undergoing Phase I clinical trial, is a new orally effective taxane with potent antitumor effects. The absorption, tissue distribution, and excretion of DJ-927 were investigated in mice, dogs, and monkeys after a single oral administration. After oral administration of [14C]DJ-927, radioactivity was rapidly absorbed, with the Cmax occurring within 1-2 h in all species. The blood and plasma radioactivity elimination was biphasic and species-dependent. Elimination half-life of plasma in dogs was much longer than those in monkeys or mice. In mice, radioactivity was rapidly distributed to all tissues except for the central nervous system, especially to adrenal glands, liver, pituitary glands, kidneys, lungs, and spleen. In all species, radioactivity was mainly excreted in feces. Following a single oral administration to mice, more than 80% of the radioactivity was excreted within 48 h; in dogs and monkeys, 80% of the radioactivity was excreted within 168 h. Urinary excretion was less than 7% of radioactive dose in all species. In vitro plasma protein binding of [14C]DJ-927 in the mouse, dog, and monkey plasma ranged from 92-98%. These studies showed that, the novel oral taxane DJ-927 was rapidly absorbed in all three species when administered by the oral route. The long biological half-life and slow elimination of radioactivity were distinctive in particular, compared with commercial taxanes. DJ-927 (as parent compound and its metabolites) is widely distributed to tissues except the brain. These preclinical data are useful for the design of clinical trials of DJ-927 and also for their interpretation.     

Preliminary data on the pharmacokinetics of Glaziovine in man

Summary The pharmacokinetic parameters of Glaziovine, a pro-aporphine alkaloid with neuropharmacological properties, were investigated in healthy human volunteers. Glaziovine-¹⁴C 20 mg was administered in capsules (oral route) and in vials (i.v. route). Total radioactivity was measured in plasma, urine and faeces. When administered orally, peak plasma levels were encountered at 2 h. The cumulative urinary excretion of total radioactivity over a 24 h period was 38% after oral and 50% after i.v. administration. Investigation of metabolites in urine revealed Glaziovine glucuronide as the sole metabolite of the drug. By comparing the percentage of urinary excretion or the area under the plasma level-time curve (AUC) obtained in the first 24 hours after i.v. and oral administration, enteral absorption was found to range from 78 to 84%. Thus, glaziovine appears to show very high enteral absorption.     

Disposition of nafimidone in rats

The absorption, distribution, excretion, and metabolism of 14C-nafimidone, a novel anticonvulsant, have been studied in rats. Nafimidone was completely absorbed following single oral doses of 10 and 100 mg/kg. After both iv and oral administration, nafimidone was rapidly eliminated from plasma (t 1/2 about 5 min), with concomitant formation of a pharmacologically active, nonconjugated metabolite, nafimidone alcohol. Systemic clearance of nafimidone from plasma after iv administration was approximately 2 times higher than hepatic blood flow in rats, and the oral bioavailability was 15%. However, the AUC of nafimidone alcohol was 30% higher after oral administration of nafimidone than that after iv administration of nafimidone. It is likely that, given its pharmacological activity, nafimidone alcohol is the more important species pharmacologically. Distribution of nafimidone-related radioactivity was widespread with highest concentrations associated with liver, kidney, adrenals, and the gastrointestinal tract. Elimination of radioactivity from tissues was rapid and complete, except that retention was noted in arterial vessels and in the ocular melanin of pigmented rats. Determination of hepatic and brain levels of nafimidone and nafimidone alcohol showed no detectable levels of nafimidone in either tissue. However, levels of nafimidone alcohol in liver and brain were as much as 13-fold and 2-fold, respectively, higher than levels in plasma. After either iv or oral administration of 14C-nafimidone, approximately two-thirds of the radioactivity was recovered in urine. The major urinary metabolites of nafimidone after a 100 mg/kg dose were characterized and shown to be dihydroxydihydronaphthalene, substituted nafimidone alcohol, and the 1-beta-glucuronide of nafimidone alcohol.     

Disposition and metabolism of indeloxazine hydrochloride, a cerebral activator, in rats

1. The disposition and metabolism of indeloxazine hydrochloride ((+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride) were studied in male Sprague-Dawley rats. 2. After oral administration of 14C-indeloxazine hydrochloride, the plasma concentration of total radioactivity reached a maximum at 15 min and declined with an apparent half-life of 2.2 h in the first 6 h period and declined more slowly thereafter. Unchanged drug in the plasma represented 13.5%, 5.9% and 0.4% of the total radioactivity at 15 min, 1 h and 6 h respectively after administration and levels decayed with a half-life of 0.9 h. 3. After oral and i.v. administration of the labelled compound, the urinary and faecal excretion of radioactivity in 72 h were 61-65% and 31-36% of the dose, respectively. Biliary excretion in bile duct-cannulated animals amounted to 49% of the dose in 72 h. 4. Seven metabolites have been isolated from the plasma or urine and characterized by i.r., n.m.r. and mass spectrometry. They were derived through dihydrodiol formation in the indene ring, hydroxylation of the indene ring and N-acetylation, oxidation and oxidative degradation of the morpholine ring. Some metabolites were excreted as their glucuronic acid or glucose conjugates. The major metabolite appeared to the trans-indandiol analogue of indeloxazine. 5. Possible metabolic pathways of degradation of the morpholine ring are discussed.     

Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans.

The absorption, metabolism, and excretion of the oral direct thrombin inhibitor, ximelagatran, and its active form, melagatran, were separately investigated in rats, dogs, and healthy male human subjects after administration of oral and intravenous (i.v.) single doses. Ximelagatran was rapidly absorbed and metabolized following oral administration, with melagatran as the predominant compound in plasma. Two intermediates (ethyl-melagatran and OH-melagatran) that were subsequently metabolized to melagatran were also identified in plasma and were rapidly eliminated. Melagatran given i.v. had relatively low plasma clearance, small volume of distribution, and short elimination half-life. The oral absorption of melagatran was low and highly variable. It was primarily renally cleared, and the renal clearance agreed well with the glomerular filtration rate. Ximelagatran was extensively metabolized, and only trace amounts were renally excreted. Melagatran was the major compound in urine and feces after administration of ximelagatran. Appreciable quantities of ethyl-melagatran were also recovered in rat, dog, and human feces after oral administration, suggesting reduction of the hydroxyamidine group of ximelagatran in the gastrointestinal tract, as demonstrated when ximelagatran was incubated with feces homogenate. Polar metabolites in urine and feces (all species) accounted for a relatively small fraction of the dose. The bioavailability of melagatran following oral administration of ximelagatran was 5 to 10% in rats, 10 to 50% in dogs, and about 20% in humans, with low between-subject variation. The fraction of ximelagatran absorbed was at least 40 to 70% in all species. First-pass metabolism of ximelagatran with subsequent biliary excretion of the formed metabolites account for the lower bioavailability of melagatran.     

Disposition and metabolism of indeloxazine hydrochloride,a cerebral activator,in rats

1. The disposition and metabolism of indeloxazine hydrochloride ((±) -2-[(inden-7-yloxy)methyl]morpholine hydrochloride) were studied in male Sprague-Dawley rats.

2. After oral administration of ¹⁴C-indeloxazine hydrochloride, the plasma concentration of total radioactivity reached a maximum at 15 min and declined with an apparent half-life of 2.2h in the first 6h period and declined more slowly thereafter. Unchanged drug in the plasma represented 13.5%, 5.9% and 0.4% of the total radioactivity at 15 min, 1 h and 6 h respectively after administration and levels decayed with a half-life of 0.9 h.

3. After oral and i.v. administration of the labelled compound, the urinary and faecal excretion of radioactivity in 72 h were 61–65% and 31–36% of the dose, respectively. Biliary excretion in bile duct-cannulated animals amounted to 49% of the dose in 72 h.

4. Seven metabolites have been isolated from the plasma or urine and characterized by i.r., n.m.r. and mass spectrometry. They were derived through dihydrodiol formation in the indene ring, hydroxylation of the indene ring and N-acetylation, oxidation and oxidative degradation of the morpholine ring. Some metabolites were excreted as their glucuronic acid or glucose conjugates. The major metabolite appcared to the trans-indandiol analogue of indeloxazine.

5. Possible metabolic pathways of degradation of the morpholine ring are discussed.     

Biliary excretion of hexachloro-1,3-butadiene and its relevance to tissue uptake and renal excretion in male rats.

Renal, biliary, pulmonary and faecal excretion experiments were carried out with labelled hexachloro-1,3-butadiene [( 14C]HCBD) in male Sprague-Dawley rats, given orally (p.o.) and intravenously (i.v.) in doses of 1 and 100 mg kg-1 as a solution in polyethylene glycol. The radioactivity excreted over 72 h was determined in rats fitted with exteriorized biliary cannulae and in rats whose bile ducts remained fully functional, respectively. In addition, bile duct-duodenum cannula-linked rats, of which the donor was given 100 mg kg-1 [14C]HCBD orally and the recipient had also a bile fistula, were examined within 30 h for radioactivity in the excreta, the kidney, the liver and the plasma. In non-cannulated rats, fractional urinary excretion decreased when the dosage increased and amounted to 23% and 8.6% after i.v. injection or 18.5% and 8.9% after p.o. administration of 1 and 100 mg kg-1, respectively. Pulmonary excretion of radioactivity was less than 9% and was not affected by the increase in dosage. In bile duct-cannulated rats, fractional urinary excretions were similar irrespective of the dose and the route of administration and amounted to ca. 7.5% of the dose. Decrease in fractional biliary excretion occurred with increase in dosage (88.7% vs 72%) after i.v. injection and (66.8% vs 58%) after gavage. In cannulated rats, faecal excretion was less than 0.5% after i.v. injection and accounted for 3% and 16% of the dose after p.o. administration of 1 and 100 mg kg-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absorption, distribution, metabolism and excretion of glucosamine sulfate. A review

This article reviews the literature related to the absorption, distribution, metabolism and excretion (ADME) of glucosamine (Gl) in man and in animals after administration of crystalline glucosamine sulfate (CGS). Intravenous administration of CGS In man, after single bolus intravenous (i.v.) injection of 1005 mg CGS (628 mg Gl), the parent Gl disappears from plasma with an apparent half life of 1.11 h. Investigations with uniformly 14C labeled Gl (14C-Gl) administered with 502 mg CGS indicate that the disappearance of Gl is due to an incorporation into the plasma globulins that occurs with a lag time of 0.45 h and a rate of 0.26 h-1. The radioactivity reaches a peak after 10 h and is eliminated with a t1/2 of 95 h. After single i.v. doses of 502 mg CGS traced with 14C-Gl, the urinary excretion in 120 h accounted for 29% of the administered dose. Consistent results are obtained in rat and dogs, in which radioactivity rapidly appears in liver, kidneys and other tissues, including the articular cartilage. In man, after i.v. bolus injection of 1005 mg CGS, the urinary excretion in 24 h of Gl determined with ion exchange chromatography was 38% of the administered dose, mostly in the first 8 h after administration. Similar results were obtained tracing CGS with 14C-Gl. Consistent results of urinary excretion were obtained in rats and dogs tracing CGS with 14C-Gl. The excretion of radioactivity in feces was small. The elimination of radioactivity with the expired air as 14CO2 measured in rats amounted to 49% of the administered dose in the 144 h following the administration, 16% of which occurred in the first 6 h. Intramuscular administration of CGS In man, a single intramuscular injection of 502 mg CGS traced with 14C-Gl, gave results similar to those after i.v. administration. Oral administration of CGS In man, after a single dose of 7.5 g CGS, Gl in plasma was below the limit of quantitation (3 micrograms/ml) of the ion exchange chromatography method. After a single dose of 314 mg CGS traced with 14C-Gl, radioactivity appeared incorporated in plasma globulins with a lag time of 1.5 h and increasing with a rate of 0.24 h-1. The peak was reached at the 9th h after administration. The radioactivity then was eliminated with a t1/2 of 58 h. The absolute oral bioavailability evaluated on the AUCs of the globulin-incorporated radioactivity was 44%. The fecal excretion in 120 h was 11.3% of the administered dose showing that at least 88.7% of the administered dose was absorbed through the gastrointestinal tract. The difference of 45% is probably due to a hepatic first-pass effect. Investigated in the rat with doses from 126 to 3768 mg CGS traced with 14C-Gl, a linear relationship was found with the AUCs as well as between doses and the Cmax of radioactivity in total and in deproteinized plasma. The urinary elimination in man of the parent Gl in 24 h determined with ion exchange chromatography after a single dose of 7.5 g of CGS was 1.19% of the administered dose, occurring mostly in the first 8 h after administration. After administration of 1884 mg repeated for 7 days the daily urinary excretion of Gl increased from 1.60% of the daily dose during the first 24 h to 2.22% of the daily dose in the last 24 h. The steady state was reached after the second day. The urinary excretion at steady state during repeated administration allowed to conclude that daily 1884 CGS administered either t.i.d. in sugar coated tablets or once a day in oral solution were bioequivalent. The elimination of radioactivity with the expired as 14CO2 measured in rats was 82% of the administered dose in the 144 h following the administration, 61% of which occur in the first 6 h. Interaction of Gl with the ADME of glucose The ADME of glucose was investigated in the rat administering i.v. or orally 14C uniformly labeled glucose. The kinetic in plasma and the tissue distribution of glucose differed totally from those of Gl, pointing out that exogenous glucose provides the energy for biochemical processes, whereas exogenous Gl acts mainly as substrate for the biosynthesis of mucopolysaccharides and of biopolymers of the articulations and bones. There was no evidence of interaction by Gl orally administered with the ADME of glucose.     

Absorption, distribution, metabolism and excretion of YM466, a novel factor Xa inhibitor, in rats

YM466 is a novel factor Xa inhibitor for the treatment of thrombosis. The absorption, distribution, metabolism and excretion of YM466 were investigated in male Fisher rats after a single oral administration. YM466 was absorbed rapidly from all segments of the gastrointestinal tract except the stomach. After oral dosing, the plasma concentration of (14)C-YM466 reached a maximum within 0.5 h, and declined rapidly with an elimination half-life of 0.64 h. The unchanged YM466 accounted for almost all of its radioactivity, suggesting a minimal metabolism in rats. This was also supported by the finding that no metabolites were observed in bile and urine after oral dosing of (14)C-YM466. The distribution of (14)C-YM466 in tissue was evaluated and the liver and kidney were the organs with radioactivity concentrations consistently higher than that of plasma. Cumulative biliary and urinary excretion of radioactivity in bile duct-cannulated rats was 29.5% and 7.6%, respectively, indicating prominent excretion into bile after oral dosing. This was consistent with the finding that 76.1% and 25.2% of radioactivity dosed were excreted to faeces and urine, respectively, after i.v. dosing. These results suggest that YM466 was rapidly absorbed and then subjected to biliary excretion with a minimal metabolism after oral dosing to rats.     

Pharmacokinetics, metabolism, excretion and plasma protein binding of 14C-levofloxacin after a single oral administration in the Rhesus monkey

Levofloxacin's metabolism, excretion, and in vitro plasma protein binding, together with its pharmacokinetics, were studied in the Rhesus monkey in support of an anthrax efficacy study in this species. Three males and three female Rhesus monkeys were dosed with a single oral dose of 14C-levofloxacin at 15 mg kg-1 (2 MBq kg-1). Following dose administration, blood samples were collected up to 48 h post-dose, and urine and faeces were quantitatively collected up to 168 h post-dose. Blood, plasma, urine, and faeces were analysed for total radioactivity. Metabolite profiling and identification was performed using radio-high-performance liquid chromatography (HPLC) and liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS). Additionally, the plasma protein binding of levofloxacin was determined in vitro by means of equilibrium dialysis. Peak plasma levels of total radioactivity and levofloxacin were rapidly reached after oral administration with a total radioactivity blood: plasma ratio close to unity. The elimination half-life of levofloxacin was estimated at about 2 h. Total radioactivity was mainly excreted in urine (about 57-86% of the dose) with faecal excretion accounting for only a minor fraction of the total amount of excreted radioactivity (about 7.4-14.7%). In the plasma, the majority of total radioactivity was accounted for by levofloxacin. In addition, two minor metabolites, i.e. levofloxacin n-oxide and presumably a glucuronide conjugate of levofloxacin, were detected. In the urine, five components were found, with levofloxacin being the major component. Minor metabolites included desmethyl levofloxacin, levofloxacin n-oxide, and a glucuronide conjugate of levofloxacin. In the faeces, the major analyte was a polar metabolite, tentatively identified as a levofloxacin glucuronide. The in vitro plasma protein binding was low (on average 11.2%) and independent of concentration (1.0-10.0 microg ml-1). No sex differences were noted in any of the investigations. The present data indicated that the metabolism and excretion pattern, and also the in vitro plasma protein binding of levofloxacin in the Rhesus monkey, were comparable with those previously reported in man, hereby supporting the use of this animal species in the efficacy evaluation of levofloxacin against inhalation anthrax. The shorter half-life of levofloxacin in the Rhesus monkey relative to man (2 versus 7 h) prompted the development of an alternative dosing strategy for use in the efficacy study.     

Pharmacokinetics of nisoldipine. I. Absorption, concentration in plasma, and excretion after single administration of [14C]nisoldipine in rats, dogs, monkey, and swine

The absorption, disposition and excretion of (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) have been studied following a single administration of the 14C-labelled compound to rats, dogs, monkey and swine via different routes (intravenous, oral, intraduodenal) in the dose range of 0.05-10 mg.kg-1. [14C]nisoldipine was absorbed rapidly and almost completely. Peak concentrations of radioactivity in plasma were reached 0.9 h (rat), 1.4 h (dog), and 3.6 h (monkey) after oral administration with normalized maximum concentrations being in the same range for all three species (0.49-0.79). The radioactivity was eliminated from plasma with half-lives between 42 h and 54 h within an observation period up to 3 days. The contribution of unchanged [14C]nisoldipine to the concentration of total radioactivity in plasma was low after oral administration (between 0.5% (monkey) and 3.4% (dog) in the peak) indicating an extensive presystemic elimination of this compound. The bioavailability was estimated at 3.4% in rats and 11.7% in dogs. [14C]nisoldipine was highly bound to plasma proteins with free fractions of 0.9-2.9%. The excretion of the radioactivity via urine and feces/bile both after oral and intravenous administration of [14C]nisoldipine occurred rapidly and almost completely within 48 h in all species. Very small residues in the body were recovered at the end of the experiments in rats and dogs (less than 1.6% of the dose). The biliary/fecal route of excretion was preferred in rats, dogs and swine, whereas in monkey 76% of the dose was excreted renally.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition of the novel serotonin agonist, LY228729, in monkeys and rats.

The disposition of a novel 5HT-1a agonist, LY228729, was studied in rats after oral administration and in monkeys after both i.v. and oral administration of a radiolabeled drug. Plasma concentrations of LY228729 declined with a half-life of 2.3 and 1.5 hr in monkeys after oral dosing and i.v. administration, respectively, and 1.9 hr in rats dosed orally. Peak plasma concentrations of the N-despropyl metabolite were greater than the parent drug following oral administration in both rats and monkeys and declined with a half-life of 3.2-3.5 hr. Plasma levels of total radioactivity rapidly exceeded that of the parent drug in both species. Radioactivity was eliminated more slowly, with terminal half-lives of 39.4 hr in the monkey and 48.6 hr in the rat. The parent drug and its despropyl metabolite accounted for only a small percentage of the total radioactivity in the plasma. Following i.v. and oral administration, radioactivity was eliminated predominantly in the urine of monkeys, but was distributed evenly between the urine and feces of rats. Parent drug and the N-despropyl metabolite were the major products in rat urine. In the monkey, the major metabolite was an uncharacterized polar compound.     

Disposition and metabolism of 2-(2'(1',3'-dioxolan-2-yl)-2- methyl-4-(2'-oxopyrrolidin-1-Yl)-6-nitro-2h-1-benzopyran (SKP-450) in rats.

The disposition and metabolism of the new antihypertensive agent 2-(2"(1", 3"-dioxolan-2-yl)-2-methyl-4-(2'-oxopyrrolidin-1-yl)-6-nitro -2H-1-benzopyran (SKP-450) were investigated in male rats after single oral and i.v. doses of 14C-labeled compound. After an oral 2.0 mg/kg dose, mean radiocarbon recovery was 98.2 +/- 2.3% with 31.1 +/- 7.3% in the feces and 67.1 +/- 14.3% in the urine. Biliary excretion of radioactivity for the first 24-h period was approximately 40%, suggesting that SKP-450 is cleared either by hepatobiliary excretion or by renal excretion. SKP-450 was well absorbed; bioavailability calculated on the basis of radioactivity was 68 to 97%. Tissue distribution of the radioactivity was widespread with high concentrations in the liver and kidney but low central nervous system penetration. Radio-HPLC analysis of bile and urine from rats indicated the extensive metabolism of SKP-450 into oxidative metabolites. Oxidative metabolism of the dioxolanyl ring resulted in an aldehyde intermediate, subsequently confirmed in vitro, which was further oxidized to the corresponding carboxylic acid (M1) or reduced to the corresponding alcohol (M3). No parent drug was detected in the urine or bile. Glucuronide conjugate of M3 was also detected in urine and bile, accounting for 5.8 +/- 2.1 and 8.9 +/- 3. 7% of the excreted radioactivity, respectively. Quantitative data obtained from plasma samples suggest that the majority of circulating radioactivity was associated with metabolites. Our results suggest that the long duration of pharmacological activity of SKP-450 (>10 h) is largely attributable to its metabolites.     

The pharmacokinetics of Oral-Turinabol in humans]

Disposition and excretion of the anabolic steroid Oral-Turinabol (1;4-chloro-17 alpha-methyl-androsta-1,4-diene-17 beta-hydroxy-3-one) were investigated in male volunteers. Following single p.o. and i.v. administration of the tritium-labelled compound the plasma concentration courses of total radioactivity (1 and 1-metabolites) and of the unchanged parent drug as well as the urinary excretion were estimated. From these data model independent pharmacokinetic parameters based on statistical moments were calculated. 1 is almost completely absorbed after p.o. administration of 10 mg per volunteer. Peak concentrations of total radioactivity and of 1 in plasma were reached about 3 h p.a. Irregularities observed in the plasma level profile following both p.o. and i.v. administration of 1 are due to a marked enterohepatic circulation. Orally given 1 is subject to a first-pass effect, resulting in a diminished systematic availability. The AUC-ratio of the unchanged drug and the total radioactivity of 1 : 13 shows the predominance of metabolites in plasma. After i.v. administration the disposition of unchanged 1 was found biphasically with a terminal half-life of 16 h. 1 and its metabolites are preferentially excreted via the kidneys. The urinary total radioactivity represented about 60% of the dose following both administrations. Due to its affinity to SHBG 1 is able to compete for the protein binding of testosterone, resulting in an increased plasma level of non protein-bound testosterone.     

Kinetics and disposition of picumeterol in animals

1. The pharmacokinetics and disposition of picumeterol, a novel β₂ receptor agonist agent, have been studied in the rat and dog following administration by inhalation, intravenous and oral routes at various dose levels.

2. Picumeterol was found to be transferred across the lung of the rat and dog following inhalation dosage. After i.v. dosage picumeterol was eliminated from plasma with a half-life of about 1?h in the rat and about 2?h in the dog. Plasma clearance in the rat was about twice liver blood flow and the plasma levels of picumeterol were low after oral administration.

3. Following instillation of ¹⁴C-picumeterol to the trachea of isolated respiring rat lung preparations radioactivity was transferred from the airways to perfusion media as unchanged drug within 2?min. After 2?h perfusion, no metabolites were detected in the recirculation perfusate or lung.

4. Picumeterol was extensively metabolized in vivo in the rat (about 95%) and dog (about 90%) and in vitro in microsomal preparations of rat, dog and human liver. O-dealkylation and β-oxidation are important as routes of metabolism.

5. Radioactivity was largely excreted in the urine of the rat and dog (> 50% of dose), as metabolites, following i.v. administration. There was some excretion of radioactivity in dog bile. Extensive first-pass metabolism was found after oral administration in the rat.     

The disposition of the local anaesthetic, pentacaine, in rats and mice

The pharmacokinetics of pentacaine, a new local anaesthetic agent from the group of carbanilates, was investigated in the rat at a dose of 2 mg kg-1 i.v. and per os. A three-compartment open model gave the best fit to the data. The model parameters are: t1/2 99.0 +/- 14.1 min, Vss 7411.1 ml kg-1, Cl 77.9 ml min-1 kg-1; after oral administration t1/2ab 4.9 +/- 1.9 min, bioavailability 59.1 per cent, and extent of absorption 79.3 per cent. Pentacaine is eliminated almost entirely by metabolism. The metabolites are excreted equally in the urine and faeces at a relatively slow rate. The pharmacokinetics of pentacaine was linear in the dose range 0.008-4 mg kg-1. The whole-body autoradiography in mice showed rapid transfer of 3H radioactivity from the vessels to tissues and a markedly heterogeneous disposition pattern in organs.     

Metabolism and disposition of moxonidine in Fischer 344 rats.

The metabolism and disposition of moxonidine (4-chloro-5-(imidazolidin-2-ylidenimino)-6-methoxy-2-methylp yrimidine ), a potent central-acting antihypertensive agent, were investigated in F344 rats. After an i.v. or oral administration of 0.3 mg/kg of [(14)C]moxonidine, the maximum plasma concentrations of moxonidine were determined to be 146.0 and 4.0 ng/ml, respectively, and the elimination half-lives were 0.9 and 1.1 h, respectively. The oral bioavailability of moxonidine was determined to be 5.1%. The metabolic and elimination profiles of moxonidine were determined after an oral administration of 5 mg/kg of [(14)C]moxonidine. More than fifteen phase I and phase II metabolites of moxonidine were identified in the different biological matrices (urine, plasma, and bile). Oxidative metabolism of moxonidine leads to the formation of hydroxymethyl moxonidine and a carboxylic acid metabolite as the major metabolites. Several GSH conjugates, cysteinylglycine conjugates, cysteine conjugates, and a glucuronide conjugate were also identified in rat bile samples. The radiocarbon was eliminated primarily by urinary excretion in rats, with 59.5% of total radioactivity recovered in the urine and 38.4% recovered in the feces within 120 h. In bile duct-cannulated rats, about 39.7% of the radiolabeled dose was excreted in the urine, 32.6% excreted in the bile, and approximately 2% remained in the feces. The results from a quantitative whole body autoradiography study indicate that radiocarbon associated with [(14)C]moxonidine and/or its metabolites was widely distributed to tissues, with the highest levels of radioactivity observed in the kidney and liver. In summary, moxonidine is well absorbed, extensively metabolized, widely distributed into tissues, and rapidly eliminated in rats after oral administration.     

Metabolism and clearance of proxicromil--studies in rat, hamster, rabbit, dog, squirrel monkey, cynomolgus monkey, baboon and man

Proxicromil was extensively metabolized and eliminated as metabolites in urine and faeces by the rat, hamster, rabbit, squirrel monkey, cynomolgus monkey, baboon and man after oral administration. The pathway of metabolism in these species was by hydroxylation of the alicyclic ring principally to yield monohydroxylated metabolites with trace amounts of a dihydroxylated product. Elimination of proxicromil by the dog, however, was essentially as the unchanged drug. The lack of metabolism of the drug by the dog resulted in the dog having a dependence on biliary excretion of the unchanged drug for clearance. These differences in clearance routes between species were reflected in the plasma clearance of the drug. The value for rat, a species capable of metabolism, was approximately 20 fold (4.1 ml min-1 kg-1) greater than the corresponding value for dog (0.2 ml min-1 kg-1). Inhibiting the metabolism of proxicromil in the rat with SKF-525A lowered plasma clearance of proxicromil (0.6 ml min-1 kg-1) and elevated the proportion of unchanged drug cleared by biliary excretion.     

Pharmacokinetics, biliary excretion, and tissue distribution of novel anti-HIV agents, cosalane and dihydrocosalane, in Sprague-Dawley rats.

Cosalane and dihydrocosalane are potent inhibitors of HIV replication with a broad range of activity. The purpose of this study was to investigate: 1) the pharmacokinetic disposition of both cosalane and dihydrocosalane in male Sprague-Dawley rats, and 2) biliary excretion, enterohepatic circulation, and tissue distribution of cosalane after i.v. and/or oral administration. Animals were administered i.v. (10 mg/kg) cosalane or dihydrocosalane through a jugular vein to obtain plasma profiles. Dose dependence of cosalane was studied over a dose range of 1.0 to 10 mg/kg. The extent of enterohepatic recycling, biliary excretion, and tissue distribution were studied after i.v. administration. Both cosalane and dihydrocosalane exhibited a biexponential disposition with very long half-lives of 749 +/- 216 and 1016 +/- 407 min, along with very large volumes of distribution 23.1 +/- 4.4 and 24.4 +/- 2. 5 liter/kg, respectively. Both cosalane (nondetectable) and dihydrocosalane (<1%) showed very poor oral bioavailability. The biliary and renal excretions of cosalane were found to be negligible with no detectable metabolites either in urine or bile. After oral administration, more than 87% of the cosalane dose was excreted in the feces as the parent compound. Also, cosalane was sequestered significantly in liver with quantifiable levels in all tissues tested, even 48 h after the dose was administered. Therefore it was concluded that the poor oral bioavailability of cosalane may be due to its poor enterocytic transport coupled with sequestration in liver parenchymal cell membrane layers.