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A sensitive and reproducible high performance liquid chromatography (HPLC)-UV method for the determination of the novel anti-tuberculosis compound 1,2:5,6-di-O-isopropylidene-3-O-(phenyl cyclopropyl methanonyl)-alpha-D-glucofuranose (S-001-14) has been developed and validated in rat serum, urine and feces. Following extraction with hexane at alkaline pH, samples were separated on a reverse phase C18 column and quantified using UV detection at 267 nm. The mobile phase was 70% acetonitrile in ammonium acetate buffer (10 mmol/L, pH 6.0) with a flow rate of 1.0 ml/min. The method was used to determine the pharmacokinetics and excretion of S-001-14 after oral doses in rats. Linearity was satisfactory over the concentration range of 5-500 ng/ml (r2, > 0.99). Recoveries were > 90% and were consistent throughout the calibration range. The precision and accuracy were acceptable as indicated by relative standard deviation ranging from 2.72 to 9.54%, bias values ranging from 1.62 to 12.05%. Moreover, S-001-14 was stable in rat serum after being subjected to three freeze-thaw cycles and for 30 days on storage at - 60 degrees C. The method was used to determine the serum concentration-time profiles for S-001-14 after oral doses of 4, 100 and 200 mg/kg in rats. A linear pharmacokinetics was found in rats at 100 and 200 mg/kg doses with a long elimination half-life (approximately 24 h), wide distribution and bioavailability of approximately 13%. The excretion study after the 100 mg/kg oral dose revealed that S-001-14 was excreted in urine (0.002 +/- 0.001%) and feces (15.6 +/- 3.5%).

The pharmacokinetics and dose proportionality of mosapride citrate ((+-)-4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl)-2-morpholinyl]methyl]benzamide citrate dihydrate, AS-4370, CAS 112885-42-4) were investigated in healthy male volunteers. The subjects were given a single oral dose (5, 10, 20 and 40 mg, each of 5 subjects) and a multiple oral dose (20 mg t.i.d. for one day, and 10 and 20 mg t.i.d. for 8 days, each of 5 subjects). Food effect on the pharmacokinetics of mosapride was also evaluated after a single oral 10 mg dose by an open, two-way crossover method. Mean plasma levels of mosapride reached a peak 0.5-1 h after single dosing of 5, 10, 20 and 40 mg. The peaks were dose-related with values of 25.1, 51.2, 157.8 and 280.6 ng/ml, respectively, and were followed by a first-order decrease with apparent half-lives of 1.4-2.0 h. The Cmax and AUC increased in proportion to the dose, indicating linear pharmacokinetics of mosapride up to 40 mg. The Cmax of M-1, a des-4-fluorobenzyl metabolite, was 1/6 of that of the unchanged drug. Urinary excretion of the unchanged mosapride and M-1 during 48 h after single dosing accounted for 0.1-0.4% and 7.0-11.0% of the dose, respectively. There were no significant changes in the plasma concentration-time profiles and urinary excretions between single and multiple doses, indicating that the pharmacokinetics of mosapride in man was not altered by its multiple administration. Plasma levels of mosapride reached steady state on day 2 of multiple administration.(ABSTRACT TRUNCATED AT 250 WORDS)

The biotransformation of 3'-chloro-2'-(N-methyl-N-[(morpholino-carbonyl)methyl]aminomethyl)benzanilide hydrochloride (fominoben-HCl, PB 89 Cl, Noleptan) was investigated in man. The most substantial metabolites were quantified. The metabolite patterns of fominoben in urine and plasma are compared. Fominoben, is rapidly and extensively metabolized to many metabolites. At the time of the maximum plasma level. 2 h after an oral dose of 160 mg of 14C-PB 89 Cl, only 1.5% of the plasma radioactivity can be measured as the unchanged initial compound. No parent compound can be found in the urine, only in the stool some traces of fominoben can be detected. The biotransformation can be characterized by four main pathways: 1. cleavage reactions, 2. hydroxylations, 3. cyclisations, 4. conjugations. The reactions 1--3 proceed as well simultaneously as successively.

The pharmacokinetics of 3'-chloro-2'-(N-methyl-N-[(morpholino-carbonyl)-methyl]-aminomethyl)benzanilide-hydrochloride (P-B 89 Cl, fominoben-HCl, Noleptan) was studied in dog and rabbit following a dose of 3 mg/kg on i.v. and p.o. administration of the 44C-labelled compound. Absorption: The compound is absorbed fast in the dog and very fast in the rabbit. Practically the entire dose is absorbed by the two species. Maximum levels in blood: dog 0.5 microgram/ml, rabbit 0.8 microgram/ml, in the plasma: dog 0.6 microgram/ml, rabbit 1.2 microgram/ml at 1--2 h p.a. and 15--30 min p.a. Elimination: The elimination from blood and plasma proceeds biphasically. 1st half-life: 1--2 h, 2nd half-life: 19--27 h (higher values for the rabbit). The dog eliminates preponderantly via the bile with the faeces, the rabbit via the kidneys: Dog: 19% in urine and 63% in faeces, rabbit 79% in urine and 16% in faeces, measured up to 96 h p.a. One rabbit excreted 70% via the urine up to 7 h p.a. The half-lives of urinary elimination are very well comparable with the figures for plasma. Biotransformation: Plasma (maximum level): Dog: Visible amounts of parent compound (M0), Rabbit: Traces M0, much M2. Urine (0--24 h p.a.): Dog: Traces: M0, Rabbit: Traces M0, much M2.