Pharmacokinetics and bioequivalence of two trimebutine formulations in healthy volunteers using desmethyl-trimebutine levels.

Trimebutine tablets (dimethylamino-2-phenyl-2-n-butyl-3,4,5- trimethoxybenzoate maleate, CAS 34140-59-5, reference) and a new tablet formulation (Eurogalena, test) were administered in 24 healthy volunteers of both sexes according to a cross-over design, in a single dose of one 100 mg tablet of each formulation. Blood samples were drawn off over a 24-h period, before (time 0) and after each administration at specific intervals. Trimebutine and its main active metabolite, desmethyl-trimebutine, were measured in plasma using a validated HPLC method with UV detection. For both compounds, the sensitivity was 20 ng.ml-1 and the analytical method was proved to be linear for concentrations between 20 ng.ml-1 and 5000 ng.ml-1, with a variability less than 11%. The non-compartmental method was used for pharmacokinetic analysis. The confidence interval approach was used for comparison of the formulations according to the EU guidance note on bioavailability and bioequivalence on Cmax, AUC0-t and AUC0-infinity, log transformed. Tmax values were statistically compared using the Friedman non-parametric test. No trimebutine concentration was measured in the plasma samples. The obtained data with desmethyl-trimebutine proved the bioequivalence of the two tested formulations.

Determination of trimebutine and desmethyl-trimebutine in human plasma by HPLC.

A simple and sensitive HPLC method has been developed to measure trimebutine (CAS 39133-31-8, maleate: CAS 34140-59-5) and its main metabolite desmethyl-trimebutine in human plasma. The method was validated according to the Washington Consensus Conference on the Validation of Analytical Methods. It involved extraction of the plasma with n-hexane containing 2-pentanol, followed by reversed-phase HPLC using a Partisil ODS2 10 microns column and UV detection at 265 nm. The retention times of the internal standard (procaine), desmethyl-trimebutine and trimebutine were 2.4, 4.3 and 6.5 min, respectively. The standard curves were linear from 20 ng.ml-1 (limit of quantitation) to 5000 ng.ml-1 for both compounds. The coefficient of variation for all the criteria of validation were less than 15%. The extraction recoveries obtained for trimebutine and desmethyl-trimebutine were about 90%. Both compounds were very stable upon storage in plasma. The method was tested by measuring the plasma concentrations following oral administration to humans during a bioequivalence study and was shown suitable for pharmacokinetic studies.

Effects of befloxatone, a new potent reversible MAO-A inhibitor, on cortex and striatum monoamines in freely moving rats.

Single administration of befloxatone (0.75 mg/kg, i.p.) in the rat increased extracellular levels of DA (+300%) in striatum. In frontal cortex, befloxatone (0.75 mg/kg, i.p.) and nialamide (100 mg/kg, i.p.) increased NA by +100% but did not modify 5HT, whereas pargyline (100 mg/kg i.p.) increased extracellular NA and 5HT by 400 and 600%, respectively. At these doses, befloxatone inhibited totally and selectively MAO-A, pargyline inhibited totally MAO-A and MAO-B. Increases of tissue and extracellular concentrations of NA and 5HT were highest after Pargyline suggesting that both monoamines may be metabolized by MAO-A and MAO-B. Befloxatone and nialamide potentiated the effects of idazoxan (20 mg/kg, i.p.) on extracellular NA in frontal cortex, which increased from 350% to 2,000 and 1,500% respectively. These results suggest that alpha 2-adrenoceptors play a major role in the regulation of extracellular NA in frontal cortex.

CRE 10904 [2-(p-fluorophenoxy), 1-(o-hydroxyphenyl)-ethane]: a new diuretic and antihypertensive drug acting by in vivo sulfation.

CRE 10904 [2-(p-fluorophenoxy), 1-(o-hydroxyphenyl)-ethane, the leading compound of a new family of loop diuretic and antihypertensive agents: 1-aryl, 2-aryloxy-ethanes] induced high-ceiling natriuretic action in dogs and rats, but was completely inactive in pigs. High-performance liquid chromatography determinations revealed that all CRE 10904 (p.o. or i.v. administered) was rapidly sulfo-conjugated in dogs and rats, and glucurono-conjugated in pigs. The (O-sulfonyl)-CRE10904 metabolite (or simply CRE 11296) rapidly appeared in plasma, reached a concentration peak at about 40 min and disappeared with a half-life time of about 3 hr. The urinary excretion of CRE 11296 was correlated with the natriuretic activity of CRE 10904. Moreover, CRE 11296 was a powerful natriuretic compound in rats and dogs and, even in pigs, i.v. CRE 11296 induced transient natriuresis (just before its rapid hydrolysis and glucurono-conjugation). Studies in human red blood cells revealed that: 1) CRE 11296 was a potent inhibitor of the [Na+,K+,Cl-]-cotransport system (IC50 of 1.5 +/- 0.3 x 10(-5) M; mean +/- S.E.M. of 5 experiments), slightly more powerful than furosemide (IC50 of 2 x 10(-5) M), 2) it was the only diuretic drug potently inhibiting the [K+,Cl-]-cotransport system (IC50 of 2.1 +/- 0.6 x 10(-5) M; N = 3) and the [Cl/HCO3-] exchanger (IC50 of 4.5 +/- 1.0 x 10(-5) M; N = 3) and 3) CRE 10904 and its glucuronide were much less potent Cl- transport inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative physiological disposition of two nitrofuran anti-microbial agents.

The physiological disposition of two nitrofuran derivatives used as antimicrobial agents for the treatment of acute infectious diarrhoea was evaluated in humans and animals. Upon administration of a single oral dose (600 mg) of nifurzide or nifuroxazide, no unchanged parent drug was detected in human blood or urine. In rats given 14C-nifurzide and 14C-nifuroxazide at a dose of 10 mg kg-1, 5 per cent and 17 per cent of the dose of nifurzide and nifuroxazide, respectively, were excreted in urine over a 48-hour period. None of this radioactivity was present as unchanged drug, indicating that renal excretion of both drugs occurs as metabolites. In the faeces 20 per cent of the radioactivity recovered was associated with unchanged nifuroxazide as compared with 100 per cent for nifurzide. Whole body autoradiography using rats showed that after oral administration of 14C-nifurzide and 14C-nifuroxazide, most of the radioactivity remained in the gastrointestinal lumen.

Metabolic pathway by cleavage of a furan ring.

14C-Diclofurime, a new Ca antagonist, was administered orally to dogs and pigs, and metabolites detected in urine and plasma. Metabolites contained in pooled urine were concentrated by column chromatography (reverse phase, gel permeation and normal phase). Chemical structures were determined by i.r. mass and 1H n.m.r. spectroscopy. The main route of Diclofurime biotransformation involved cleavage of the furan ring. Subsequent biotransformation steps involved N-deethylation in the side-chain and O-demethylation in the aromatic moiety of the drug. The major pathway is unusual for molecules with a furan heterocycle.