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

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

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

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

Pharmacokinetics and metabolism of the cholecystokinin antagonist dexloxiglumide in male human subjects.

1. Mean concentrations of total (14)C and of dexloxiglumide at the end of single 20-min infusion doses of (14)C-dexloxiglumide (200 mg) to four healthy male subjects were 18.5 microg eq x ml(-1) and 19.5 microg ml(-1) respectively. The mean plasma clearance (0.22 l h(-1) x kg(-1)) and mean volume of distribution (V(ss) = 0.18 l kg(-1)) were low. 2. Single oral doses of a solid formulation of (14)C-dexloxiglumide (200 mg) to the same subjects appeared to be rapidly and well absorbed. Mean peak plasma concentrations (C(max)) of total (14)C (2.8 microg eq x ml(-1)) and of dexloxiglumide (2.2 microg x ml(-1)) occurred at about 1.5 h. Systemic availabilities of the oral dose based on total (14)C and dexloxiglumide were 70 and 48%, respectively. Thus, a proportion of an oral dose was subjected to presystemic elimination and the absorbed dose mainly eliminated by metabolism. Binding of dexloxiglumide to plasma proteins was extensive (96.6-99.2%). 3. Total (14)C was excreted mainly in the faeces. Mass balance of (14)C excretion was almost complete within 7 days when a mean of > 93% of the dose had been recovered. After the intravenous (i.v.) dose, mean totals of 23.7 and 69.8% of the dose were excreted in urine and faeces, respectively, during 7 days, and 19.5 and 73.7% of the dose, respectively, after the oral dose. The data were consistent with biliary excretion and perhaps some enterohepatic circulation of conjugates of dexloxiglumide and at least one of its metabolites. 4. LC-MS/MS of urine extracts showed that dexloxiglumide was metabolized by oxidation and conjugation. The former included at least two metabolites formed by monohydroxylation in the N-(3-methoxypropyl) pentyl side chain, and O-demethylation of this side chain followed by subsequent oxidation of the resultant alcohol to the dicarboxylic acid. At least one glucuronide was also present in urine. The main components in faeces appeared to be dexloxiglumide and a dicarboxylic metabolite formed by O-demethylation followed by oxidation of the N-(3-methoxypropyl) side chain. Both compounds were identified as their corresponding methyl esters formed because acid and methanol were used in the extraction procedure. Dexloxiglumide and the dicarboxylic acid were presumably excreted in bile as the glucuronic acid conjugates.

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).

Validation of a liquid chromatographic-tandem mass spectrometric method for the measurement of (R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl]-3-(3-methylaminophenyl)urea (YF476) in human plasma.

A sensitive and specific liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method has been validated for the measurement of YF476 in human plasma. The method involves a simple liquid-liquid extraction procedure, chromatography of the extracts on a C(18) column, atmospheric pressure chemical ionisation and detection in the multiple reaction monitoring mode. The calibration line was linear over the concentration range 0.1 ng/ml (the limit of quantification) to 25.0 ng/ml. Intra- and inter-batch precision was <14% and intra- and inter-batch accuracy was <11% over the entire calibration range. The bioanalytical method is robust and has been used for the analysis of many samples from human subjects involved in early clinical studies (Phase I).

Pharmacokinetics of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist. 4th communication: tissue distribution, placental transfer and milk secretion of radioactivity in rats after a single oral administration of 14C-NS-49, and effects of repeated administration on its pharmacokinetics.

The tissue distribution, placental transfer and milk secretion of 14C-NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoro-methanesulfonanilide hydrochloride, CAS 137431-04-0), a phenethylamine class alpha 1A-adrenoceptor agonist, have been studied after a single oral administration (1 mg/kg) of a suspension formulation to rats. Radioactivity concentrations in tissues were generally highest 1 or 4 h, and for most tissues, exceeded those in the corresponding plasma. Concentrations were generally similar in male and female rats and persisted for at least 24 h. Radioactivity concentrations in most tissues declined in parallel with those in plasma. Placental transfer of radioactivity was low accounting for < 0.1% of the maternal dose. In milk, concentrations were of a similar order to those in the plasma but reached a peak later: the data implied that 14C-NS-49 readily diffused from the plasma into the milk. The absorption, distribution and excretion of 14C-NS-49 have been studied after the repeated administration (1 mg/kg) of a suspension formulation to rats for up to 21 days. At 21 days, radioactivity concentrations in plasma reached a peak 1 h and declined with a terminal half-life of 67 h. Steady state concentrations were reached during 14 days. Peak concentrations in tissues occurred 1 h and, in most tissues exceeded the plasma value. Radioactivity concentrations in tissues appeared to reach steady state during the 21-day dosing period. Tissue and blood cell concentrations declined more slowly than those in the plasma. Radioactivity excretion was relatively constant during the repeated administration and similar in urine (mean 45.8% total dose) and feces (mean 48.2% total dose). At 7 days after the last of 21 daily oral doses, only 0.2% of the total dose remained in the body, indicating that there is no marked accumulation of radioactivity in the tissues. The results obtained in these studies indicated that rats receiving NS-49 at 24 h intervals during chronic and reproductive toxicity studies would be continually exposed to the parent compound and/or its metabolites.

Identification of cytochrome P450 isozymes involved in metabolism of the alpha1-adrenoceptor blocker tamsulosin in human liver microsomes.

1. The in vitro human liver metabolism of the alpha1-adrenoceptor blocker tamsulosin was investigated. When 14C-tamsulosin was incubated with human liver microsomes, it was converted to five known urinary metabolites and at least three unknown metabolites. Of the former group, the predominant metabolite was the O-deethylated metabolite (M-1), followed by the o-ethoxyphenoxy acetic acid (AM-1) and the m-hydroxylated metabolite (M-3). 2. There was a good linear relationship between AM-1 formation and testosterone 6beta-hydroxylase activity in microsomes from each of 10 individual donors. The rate of M-1 formation also correlated with the same activity, albeit the correlation curve did not pass through the origin. By contrast, the rates of M-3 and the O-demethylated metabolite (M-4) formation correlated with dextromethorphan O-demethylase activity. 3. Ketoconazole strongly inhibited AM-1 formation and reduced that of M-1 by c. 60%. Immunoinhibition studies using anti-rat antibodies supported these results. The formation of M-3 and M-4 was inhibited by quinidine and sparteine. 4. It is concluded that formation of tamsulosin metabolites, AM-1 and M-1, is catalysed by CYP3A4 whereas that of M-3 and M-4 is catalysed by CYP2D6. However, minor contributions from other CYPs cannot be excluded.

Absorption, metabolism and excretion after oral administration of a new Ca antagonist, 14C-benidipine hydrochloride to man.

1. In healthy male volunteers, the absorption, metabolite profiles and excretion of 14C-benidipine hydrochloride, a new Ca antagonist, were investigated after oral administration at a dose of 8 mg. 2. 14C-benidipine hydrochloride was rapidly absorbed, and the plasma concentration of radioactivity and unchanged drug reached a maximum of 71.2 ng eq./ml at 1.1 h and 2.56 ng/ml at 0.6 h respectively, and then declined bi-exponentially. The half-life in the elimination phase was 14.7 and 5.3 h respectively, AUC of unchanged drug was low, about 1% of that of radioactivity. 3. Five days after administration, 36.4% of the administered radioactivity was excreted in urine and 58.9% in faeces. 4. The metabolite profiles in plasma, urine and faeces were analysed by hplc. At 1 h after administration the predominant metabolites in plasma were M9 and M2, which accounted for 13.8 and 8.2% of the radioactivity respectively, whereas unchanged drug represented 1.2%. Predominant metabolites in urine 12 h after administration were M3 and M8, which accounted for 2.22 and 2.21% of the administered radioactivity respectively. Metabolites excreted in faeces 120 h after administration were very complex and poorly separated by hplc and could not be characterized: unchanged drug was not detected in the faeces.

Oncogenicity studies of the new serotonin (5-HT)3-receptor antagonist ramosetron in mice and rats.

Oncogenicity studies of ramosetron ((R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazol e hydrochloride, CAS 132907-72-3, YM060), a new compound having serotonin (5-HT)3 receptor antagonist activity, were carried out in male and female mice and rats. Six groups (two control and four treated) of B6C3F1 mice and F344 rats were given YM060, dissolved in distilled water, once daily by oral intubation at doses of 0, 1, 10, 30 and 100 mg/kg/d. Toxicokinetics indicated that sufficient exposure of the animals to the test material was achieved during the oncogenicity studies. Cmax and AUC of YM060 at 100 mg/kg/d were in the range of 3-5 micrograms/ml and 8 micrograms.h/ml in mice, 1-5 micrograms/ml and 7-16 micrograms.h/ml in rats, respectively. The administration of YM060 resulted in a slightly increased mortality rate among female rats treated with 30 or 100 mg/kg/d, particularly during the Weeks 38-87. Body weights of the high-dosed male and female rats during the Weeks 36 to 96 were significantly decreased when compared to controls. An approximately 30% suppression of body weight gain was recorded during Weeks 36-96 for both male and female rats, and 15% suppression of body weight gain was recorded during Weeks 0-104 for male mice. There was no evidence of a treatment-related effect on the incidence of any tumor or tumor type, and there were no non-neoplastic findings considered to be related to the administration of YM060. All microscopic changes seen in mice and rats were of the usual type commonly occurring in untreated aged B6C3F1 mice and F344 rats. In conclusion, there was no evidence of an oncogenic effect of YM060 in mice and rats.

Effect of the cephalosporin cefepime on hepatic drug metabolising enzyme activity in rats.

Oral doses of the new cephalosporin cefepime administered to rats for 14 days (40 mg/kg/day) did not affect the activities of the hepatic drug metabolising enzymes measured. By contrast there were highly statistically significant increases in all measured parameters in rats treated with phenobarbitone (80 mg/kg/day), the positive control. Control activities in male rats exceeded those in females by about 2-3 fold.

Metabolic fate of 14C-camostat mesylate in man, rat and dog after intravenous administration.

1. The metabolic fate of N,N-dimethylcarbamoylmethyl 4-(4-guanidino[14C]benzoyloxy)phenylacetate methanesulphonate (14C-camostat mesylate) was investigated after i.v. administration to man (12-h infusion), and to rat and dog (bolus injection). 2. Renal excretion (mainly in 24 h) accounted for at least 80% dose in all three species, and the only two important metabolites were identified as 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) and 4-guanidinobenzoic acid (GBA). 3. Parent drug was not detected in human plasma either during or after infusion of 14C-camostat mesylate owing to rapid hydrolysis of the side-chain ester group (t1/2 < 1 min). Steady-state levels of both GBPA and GBA in plasma were apparently attained by the end of the infusion period. Mean terminal half-life, systemic clearance and apparent volume of distribution at steady-state of GBPA in man were 1.0 h, 6.4 ml/min per kg and 0.38 l/kg, respectively, and the corresponding values for GBA were 2.4 h, 4.7 ml/min per kg and 1.01/kg respectively. 4. Radioactivity was rapidly distributed to most tissues after bolus i.v. doses of 14C-camostat mesylate to rats and dogs, with highest levels being associated with the liver and kidney, the two main organs of drug elimination. Concentrations in the pancreas, a possible site for drug action, were generally lower than those in plasma.

Disposition of the novel anticancer agent vinorelbine ditartrate following intravenous administration in mice, rats and dogs.

1. KW-2307 (vinorelbine ditartrate, CAS71486-22-1) is a new semisynthetic antitumour vinca alkaloid. Its pharmacokinetics, distribution and excretion were investigated following intravenous administration to mice (1.2 mg/kg), rats (0.12 and 1.2 mg/kg) and dogs (0.4 mg/kg). Dose levels are expressed as the free base. 2. Plasma concentrations of drug-related radioactivity declined in a bi- or tri-exponential manner, initially rapidly and then slowly (half-life of 35 h or more). Unchanged drug concentrations declined with terminal half-lives of 35.8 h in rats and 34.5h in dogs: a terminal phase was not observed in mice. KW-2307 can be characterised as a drug of high clearance (3.78, 1.73 and 1.20 l/h/kg in the mice, rats and dogs, respectively) and large volume of distribution (12.7, 41.9 and 49.6 l/kg in the mouse, rat and dog, respectively). After repeated administrations for 21 days in the rat, the accumulation ratio for unchanged drug concentrations in plasma was 1.5. 3. The extent of binding of 3H-KW-2307 in vitro to proteins in the plasma of humans, dogs, rats and mice was 89, 90, 93 and 97%, respectively. 4. In rats, concentrations of radioactivity in most tissues exceeded those in plasma, and at 0.5 h after administration were greatest in the adrenals, thyroid, pituitary, lungs, small intestine contents and kidneys. The lung is a target for drug action. Concentrations of radioactivity in the brain were lowest. In pregnant rats, placental transfer of radioactivity was low, less than 1% of the dose. Concentrations in mammary tissue, another target for drug action, exceeded those in plasma. The tissue distribution profile of radioactivity in rats was similar after single and repeated administrations. 5. Radioactivity was excreted mainly in faeces (61-73% dose in 48 h and 71-79% dose in 168 h). Biliary excretion accounted for 42.6% dose in rats during 48 h although enterohepatic cycling was probably unimportant.

Distribution of the recombinant coagulation factor 125I-rFVIIa in rats.

Recombinant human factor VIIa (rFVIIa; NovoSeven) is a two-chain activated clotting factor that is used in the treatment of haemophilia. The distribution of radioactivity in male and pregnant and non-pregnant female rats has been examined by whole-body autoradiography (WBA) after single intravenous doses of 125I-radiolabelled rFVIIa at a dosage level of ca. 0.1 mg/kg. Concentrations of radioactivity were highest in the blood and the highly perfused major thoracic and visceral organs and gonads. This distribution of radioactivity was generally similar in pregnant and non-pregnant females, and although radioactivity was concentrated in the foetal thyroid, it was present in other foetal tissues only at trace levels. Radioactivity in thyroid, urinary bladder and gastrointestinal tract of all rats was apparently associated with detached 125I-iodide. At early sacrifice times (up to 2 h), radioactivity was present in the bone marrow, but at later times (6-24 h) it was apparently associated with the mineralised bone structures. The quantitative distribution of total and trichloroacetic acid precipitable radioactivity in the tissues of rats also was studied after single intravenous doses of 125I-rFVIIa and 125I-rFVII, the non-activated single chain precursor of FVIIa, which is normally present in the circulation. These studies confirmed the WBA findings and showed that the tissue distribution of 125I-rFVII and 125I-rFVIIa was similar, indicating that the distribution of rFVIIa during therapy would be similar to that produced from endogenous FVII as a physiological response to vascular injury.

Relationship between pharmacokinetics and pharmacodynamics of tinzaparin (logiparin), a low molecular weight heparin, in dogs.

1. Pharmacodynamic models relating the plasma concentrations (C) of radioactive heparin material to anticoagulant effect (E) have been investigated after single i.v. and s.c. doses of 3H-tinzaparin (1 and 4 mg/kg), a radiolabelled low molecular weight heparin, to six dogs. 2. A counterclockwise hysteresis, characterizing the C versus E relationship, was observed in all animals after s.c., but not i.v., doses indicating a possible delay (lag-time) in the systemic availability of pharmacologically-active heparin material following extravascular administration. A constant (Ke) was introduced into the model to account for this hysteresis. 3. At high plasma concentrations of radioactivity (> 10 micrograms/ml), E was related to C by a sum of two sigmoid Emax models, whereas, at lower concentrations, this reduced to the well-known sigmoid Emax model. It was proposed that tinzaparin activates two 'receptors' having different affinities for the drug. The values of EC50 associated with the activation of a single 'receptor' and of a proposed additional 'receptor' were 3 and 13 micrograms/ml of heparin material, respectively. 4. Heparin material was predominantly eliminated by renal excretion and underwent widespread tissue distribution. After s.c. administration, input of heparin material into systemic plasma was complete within 12 h post-dose, and the absorption process was characterized by a bi-exponential function. 5. We conclude that sigmoid Emax models adequately describe the C versus E relationship after s.c. and i.v. doses of 3H-tinzaparin in dogs and that the interindividual variation of the pharmacodynamic parameters derived from this model was relatively small.

Metabolism of the anti-psoriatic agent 5-methoxypsoralen in humans: comparison with rat and dog.

1. Single oral doses of 14C-5-methoxypsoralen (5-MOP) to human subjects (50 mg), rats (1 mg/kg) and dogs (1 mg/kg) were fairly well absorbed but subjected to extensive first-pass metabolism, at least in rat and human. Means of 62, 51 and 40% dose in urine and 31, 38 and 48% dose in faeces, were excreted by humans (during 5 days), rats (3 days) and dogs (1 day), respectively. In dogs, faecal 14C was probably derived, in part, from biliary excreted material. 2. Total 14C in human plasma reached peak concentrations after 2 h (mean 235 ng 5-MOP equivalent/ml) and declined relatively slowly, to about 60% of this value within 24 h. Unchanged 5-MOP was not detected in plasma using h.p.l.c. (< 5 ng/ml). 3. Tissue concentrations of 14C were generally greater in dogs than rats and reached peak levels at 1 h in dogs but at 24 h in rats. Apart from liver and bile, dog tissue 14C concentrations were lower than those in the corresponding plasma, whereas in rat they were lower only until the time of peak concentrations, after which they were generally greater. 4. 5-MOP was extensively metabolized in all three species. The major 14C-components in human and dog urine were glucuronic acid conjugates, mainly of an arylacetic acid and arylalcohols, resulting from initial oxidative metabolism of the furan ring of 5-MOP. In rat, these metabolites were excreted mainly unconjugated. An unusual metabolite was formed by reduction of the lactone moiety of 5-MOP, probably by the gut flora, giving rise to an arylpropionic acid, excreted as a glucuronic acid conjugate in the urine of all three species. 5. Unchanged drug was a very minor component of human and rat plasma, but a major component of dog plasma. In all three species, circulating 14C-metabolites were similar to those in the urine but were present mainly unconjugated. On the basis of these data, the metabolic fate of 5-MOP in humans was more similar to that in dog than to that in rat, although humans appeared to metabolize 5-MOP more rapidly than did dog.

Percutaneous absorption of co-administered N-methyl-2-[14C]pyrrolidinone and 2-[14C]pyrrolidinone in the rat.

The percutaneous absorption has been investigated in rats of a mixture (3:2, w/w) of N-methyl-2-pyrrolidinone (NMP) and 2-pyrrolidinone (2-P), a combination intended for use as a vehicle in the formulation of an antimycotic drug to enhance skin penetration on dermal application, following co-administration of the two 14C-radiolabelled compounds by the dermal and oral routes. Radioactivity was excreted predominantly in the urine after either route of administration, and comparison of the respective excretion profiles indicated that about three-quarters of the applied dose was absorbed through the skin. Plasma concentrations of each parent compound, as determined by radio-HPLC, reached peak values at 2 hr after oral dosing, and remained relatively uniform during 1-6 hr after application to the skin, suggesting constant percutaneous absorption during this period. NMP appeared to be absorbed through the skin more extensively and at a slightly faster rate than 2-P; total percutaneous absorption tended to be more extensive in female than in male rats. Together, these two 14C-compounds accounted for most of the plasma radioactivity up to 6-8 hr post-administration. However, by 12 hr (when plasma levels were relatively low), most of the radioactivity was associated with unknown polar metabolites. In view of the extensive percutaneous absorption and little first-pass metabolism of the two pyrrolidinones, the oral route was considered to represent a valid alternative to the dermal route for the assessment of the systemic toxicity of the two compounds.

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.

Pharmacokinetics of the anti-inflammatory drug ximoprofen in healthy young and elderly subjects: comparison with elderly rheumatic patients.

The pharmacokinetics of ximoprofen were studied in young and elderly subjects after single and repeated doses up to 30 mg. In healthy elderly subjects (30 mg dose), a mean peak plasma drug concentration of 1.78 micrograms ml-1 +/- 0.83 s.d. occurred at a mean time of 1.95 h +/- 1.40 s.d. and, thereafter, concentrations declined monoexponentially with a mean half-life of 3.8 h +/- 1.4 s.d. Comparison of these data with those from younger healthy subjects showed that peak drug concentrations, areas under the curve and half-lives were about two-fold greater in the elderly, these differences probably reflecting a lower systemic drug clearance. Similar results were obtained on comparing data from young healthy subjects and elderly rheumatic patients receiving single and repeated doses of ximoprofen (15 mg twice daily). In patients, the half-life of ximoprofen was 2.5 h +/- 0.7 s.d. Within either group, pharmacokinetic parameters after single or repeated doses were similar: ximoprofen did not accumulate in the plasma of the young or elderly.

Pharmacokinetics of the anti-inflammatory drug ximoprofen in healthy subjects and in disease states.

The pharmacokinetics of ximoprofen, a potent new non-steroidal anti-inflammatory agent, has been investigated in normal healthy subjects and in patients with hepatic or renal disease. After intravenous infusion of 22.8 mg to healthy subjects, plasma ximoprofen concentrations declined in a polyexponential manner with a terminal phase half-life of 1.9 h. The systemic clearance of ximoprofen was 115 ml.min-1 and the volumes of distribution were 18.01 Vz and 13.81 Vss. Ximoprofen was 80-90% bound to plasma proteins. The systemic availabilities (f) of orally and rectally administered doses of 30 mg of ximoprofen were 98% and 56% respectively and, in the case of the rectal dose, absorption appeared to be prolonged leading to "flip-flop" kinetics. After single oral doses of 30 mg of ximoprofen to patients with hepatic disease, half-life (2.2 h), peak plasma concentrations (1.55 micrograms.ml-1 cf 1.04 micrograms.ml-1 in healthy subjects) and areas under the curve (6.12 micrograms.h.ml-1 cf 3.54 micrograms.h.ml-1 in healthy subjects) were significantly different from those in healthy subjects. After single oral doses of 30 mg of ximoprofen to patients with renal disease, pharmacokinetic parameters of half-life (4.0 h), mean residence time (6.0 h) and area under the curve (9.2 micrograms.h.ml-1) were significantly different from those in healthy subjects. There were no significant differences in pharmacokinetic parameters between patients having differing degrees of renal disease. These data nevertheless suggest that accumulation of ximoprofen in hepatic or renal disease would be of slight or negligible clinical relevance and that no alteration of the dose regimen (up to 15 mg twice daily) may be required when ximoprofen is administered in these disease states.