Metabolism of dimetindene in rats.

The preparative separation of dimetindene (CAS 5636-83-9) enantiomers was achieved by fractionated crystallization of the diastereomeric tartrate salts. HPLC on alpha-AGP (alpha 1-acid glycoprotein) was used for confirmation of the enantiomeric purity. After administration of the enantiomers to rats the AUC and Cmax of S(+) dimetindene and (-)N-demethyldimetindene were slightly increased. In agreement with the serum concentration data significantly more (-)N-demethyldimethindene was excreted into urine after administration of the individual enantiomers. S(+) dimetindene was metabolised to a lesser extent in vivo (see above) as well as in vitro in rat liver homogenate. After prior enzyme induction conversion of the enantioselectivity with respect to unmetabolised dimetindene occurred. 6-Methoxydimetindene, 6-hydroxydimetindene and 6-hydroxy-N-demethyldimetindene were synthesized. 6-Methoxydimetindene is likely to be a metabolite since the retention times of synthetic compound and the substance extracted from serum and urine are identical. The formation of 6-hydroxy-N-demethyldimetindene was proved for the first time by comparison of the mass spectra of metabolite isolated from in vitro incubations and synthetic compound after derivatisation with acetic anhydride.

Quantification of dimethindene in plasma by gas chromatography-mass fragmentography using ammonia chemical ionization.

A gas chromatographic-mass fragmentographic method using ammonia chemical ionization for the determination of dimethindene in human plasma is described. The drug was isolated from plasma by liquid-liquid extraction with hexane-2-methylbutanol. Plasma components were separated on a capillary column coated with chemically bonded methyl silicone. For detection of dimethindene, its quasi-molecular ion (M + H+) was mass fragmentographically monitored after chemical ionization with ammonia as reagent gas. Dimethindene was quantified using methaqualone as the internal standard: the quantification limit in plasma was 0.2 ng/ml, the within-run precision was 8.0% and the inter-run precision 5.6%. The plasma concentration-time profile was established after a single dose of 4 mg of dimethindene with an average maximum concentration of 5.5 ng/ml, detectable up to 48 h post application.

High-performance liquid chromatographic method for the determination of dimethindene in urine.

An automated high-performance liquid chromatographic assay, using on-line solid-phase extraction, is described for the determination of dimethindene in urine. The solid-phase extraction of the sample (1000 microliters) and the elution of the drug on to the analytical column are performed automatically and concomitantly. The limit of quantification is 5 pmol/ml.

Pharmacokinetic study of 14C-letosteine in man after oral intake and steady-state.

Based on previous animal and on preliminary human results a further human study was performed in order to confirm the relevant pharmacokinetic parameters and the lack of accumulation of letosteine after repeated administrations. Thus, six healthy male volunteers were given a single oral dose of 50 mg (100 microCi) 14C-letosteine in form of gelatine capsules. A treatment lasting 11 days to obtain a steady-state was started three days later with three similar daily oral doses of unlabelled letosteine. Then, one capsule of 14C-letosteine was administered again. The radioactivity of blood, plasma, urine and expired air was measured at regular intervals after both radioactive doses. Several pharmacokinetic parameters were calculated for the single oral intake and for the oral intake at steady state. The results show a good absorption rate of letosteine since about 90% of the dose was found in the urine. Elimination was biphasic, with half-lives of about 1 and 4 hours in blood and plasma. No striking differences were recorded between the single oral intake and the oral intake at steady state for the various parameters assessed: Cmax, Tmax, AUC, Aeurine and AeCO2. It was therefore concluded that repeated doses of letosteine did not influence the absorption, the distribution, the metabolism and the elimination processes.

Pharmacokinetics of dimetindene after intravenous and oral administration to healthy volunteers.

The pharmacokinetics of dimetindene (dimethindene maleate, Fenistil, CAS 3614-69-5) were studied after its intravenous and oral administration to 8 healthy male volunteers. Serum concentrations were measured for 48 h using an enzyme-linked immunosorbent assay. Pharmacokinetic parameters (AUC, t1/2, CLs, Vd and F) were calculated using the clearance approach.

Identification of the molecular structure of the phenolic primary metabolite of dimetindene in animals and man.

The metabolic pathway of dimetindene (dimetindene maleate, Fenistil), an antiallergic drug commercially available for more than 20 years, has remained unknown. By means of HPLC, GC-MS and MS-MS, dimetindene was found to be hydroxylated on the indene moiety of the molecule both in vitro with hepatic microsomes of several species and in vivo in man. Cochromatographic analysis (HPLC and GC-MS) of the primary metabolites produced in vitro and in vivo demonstrated their similarities but revealed differences from the chemically synthesized 5-hydroxy-dimetindene. Using large volumes of in vitro incubations of rat microsomes with dimetindene and cofactors, 1.15 mg of pure primary metabolite were first produced and then extensively purified. The study of the NMR proton in one and two dimensions (COSY) clearly demonstrated that this metabolite is hydroxylated on the C6 of the indene moiety as compared to the C5 for the synthetic product.

Influence of food and antacid administration on fluoride bioavailability from enteric-coated sodium fluoride tablets.

The relative bioavailability of enteric-coated sodium fluoride (NaF) tablets (10 mg F-) has been assessed following administration with a standard calcium-rich breakfast or calcium-poor lunch, and 2 h before or simultaneously with antacid administration (2.4 g aluminum-magnesium hydroxide), versus intake on an empty stomach. Twelve volunteers were studied 3 times according to an open, three-way crossover design over a 24 h period at weekly intervals. Meals were found to decrease the peak serum concentration of NaF from 122 micrograms/L during fasting (after baseline subtraction) to 71 and 88 micrograms/L with breakfast and lunch respectively, and to slow its absorption rate with Tmax increasing from 3.3 to 7.3 and 11.2 hours, without altering its bioavailability. Antacid impaired the bioavailability of NaF by 80% when administered simultaneously, with AUC decreasing from 987 to 155 micrograms.h/L, but had no significant effect when taken 2 h before NaF. In conclusion, the enteric-coated NaF tablets used in this study can be administered with food or after a 2-hour delay following antacid administration, but should not be taken simultaneously with antacid.

Lactitol: gastrointestinal absorption and effect on blood lactate in healthy volunteers and patients with cirrhosis.

The gastrointestinal absorption of lactitol has been studied in 6 healthy volunteers and 8 patients with cirrhosis. Following administration of lactitol 0.5 g/kg, no lactitol was found in serum. The urinary excretion of lactitol over 24 h ranged from 0.1 to 1.4% of the administered dose (0.46% in cirrhotics and 0.35% in healthy volunteers). Blood D- and L-lactate and plasma glucose did not increase following lactitol. The data indicate that lactitol was poorly absorbed from the gastrointestinal tract in healthy volunteers and patients with cirrhosis, and that the disaccharide did not disturb glucose or lactate homeostasis.

The disposition and metabolism of (+)-cyanidanol-3 in patients with alcoholic cirrhosis.

The effect of alcoholic cirrhosis of the liver on the disposition and metabolism of (+)-cyanidanol-3 has been studied in three patients. Following oral intake of U-14C-(+)-cyanidanol-3 2 g, the unchanged drug was detected in plasma between 0.5 and 24 h after dosing and the metabolites, measured only as 14C-levels, were still detectable at 120 h. A mean of 55% of the dose was excreted in the urine, in which the major metabolites were the glucuronic and sulphuric acid conjugates of (+)-cyanidanol-3 and 3'-O-methyl-(+)-cyanidanol-3, although one patient excreted a larger proportion as non-conjugated metabolites. The pattern of metabolism in the patients did not differ significantly from that in control subjects, suggesting that the drug is handled by the cirrhotic liver in a similar manner to the normal liver.

Determination of pilocarpine by HPLC in presence of isopilocarpine a pH-sensitive polymer in ophthalmic dispersions.

Quantification of pilocarpine in the presence of the epimer isopilocarpine in polymeric dispersions is reported. The method describes a technique using reversed-phase HPLC and UV detection of pilocarpine in the presence of a pH-sensitive polymer. As this method does not require prior sample preparation it will be of special interest for process control and development.

Treatment of liver disease with malotilate. A pharmacokinetic and pharmacodynamic phase II study in cirrhosis.

Malotilate, a sulphur-containing compound with antifibrotic and hepatoprotective properties in several animal models, has been investigated in cirrhotic patients. Nine patients with cirrhosis of various aetiologies and severity, and 4 healthy volunteers, participated in a pharmacokinetic study. After a single dose of 500 mg malotilate p.o. peak malotilate plasma concentration measured by GC-MS was 35 times higher in patients (median 0.70 micrograms/ml) than in controls (median 0.019 micrograms/ml). The median apparent oral clearance was approximately 50 times lower in cirrhotics (median 2.21/min) than in healthy volunteers (1181/min). The apparent oral clearance was significantly correlated with indicators of portal-systemic shunting, such as the 2-h postprandial serum bile acids and the bioavailability of oral nitroglycerine. Urinary output of the glucuronidated metabolite-(M3), measured by HPLC, was normal in patients, whereas recovery of metabolite-M6 (resulting from ring opening and loss of sulphur) was reduced. Six patients in an open 6-month trial received malotilate 200 mg t.i.d. for 2 months and 400 mg t.i.d. for 4 months. The thrombocyte count increased and serum ferritin level fell in all patients, and serum cholinesterase rose and IgA decreased in 5 of 6. The other indicators of liver function did not show a significant change. Dry skin was the only possible adverse effect. It is concluded that first-pass elimination of malotilate is dramatically reduced in cirrhotics, and that a smaller amount of the drug reaches the liver in such patients. Malotilate was well tolerated, even in patients with advanced disease.

The quantitative disposition of 3-O-methyl-(+)-[U-14C]catechin in man following oral administration.

Three young male volunteers excreted 51.5, 33.6 and 55.9% of a single 2 g oral dose of radiolabelled 3-O-methyl-(+)-catechin in urine within 120 h of administration. Excretion of the unchanged compound, however, accounted for only 0.7, 0.1 and 0.2% of the dose. The major urinary metabolites were glucuronides of 3,3'-O-dimethyl-(+)-catechin (15.8% dose) and a glucuronide and a sulphate of 3-O-methyl-(+)-catechin (11.4% and 10.6% dose, respectively). No evidence for demethylation was obtained. 3-O-Methyl-(+)-catechin was detected and measured in plasma by h.p.l.c. 0.5-12 h after administration. Peak levels (11-18 micrograms/ml) were attained within two hours of administration and the half-life of removal from plasma was approx. 140 min. Metabolism of 3-O-methyl-(+)-catechin in man was found to vary significantly from other species, as methylated metabolites (3'-O-methyl ethers) in man represented only about 53% of the urinary metabolites, whereas in the mouse, rat and marmoset, 3'-O-methylation was almost quantitative (Hackett and Griffiths 1981). The glucuronic acid conjugates of 3-O-methyl-(+)-catechin detected in man also differed from those previously reported in the rat. Additionally, sulphate conjugation of 3-O-methyl-(+)-catechin was observed in man although not in other species. 3-O-Methyl-(+)-catechin, unlike (+)-catechin, did not undergo ring fission.

The metabolism and excretion of (+)-[14C]cyanidanol-3 in man following oral administration.

Following administration of a single dose of [U14C]cyanidanol-3 to human volunteers, a mean of 55% of the dose of 14C was excreted in urine; 90% of urine 14C was excreted within 24 h of drug administration. The major urinary metabolites were the glucuronides of (+)-catechin and 3'-O-methyl-(+)-catechin, and the sulphate of the latter. These three conjugates collectively accounted for three quarters of urine 14C. Urinary excretion of unchanged (+)-cyanidanol-3 was 0.1-1.4% dose. (+)-Cyanidanol-3 and metabolites containing the intact flavanol ring system accounted for 90% of urine 14C. Ring scission was, under these conditions, a minor metabolic pathway resulting in the excretion of small amounts of 3-hydroxybenzoic acid, 3-hydroxyhippuric acid and 3-hydroxyphenylpropionic acid. Unchanged (+)-cyanidanol-3 was detected in plasma between 30 min and 12 h after administration. Metabolites (as total 14C) persisted in plasma for at least 120 h after administration.

Identification of the major urinary metabolites of (+)-catechin and 3-O-methyl-(+)-catechin in man.

Following oral administration of (+)-catechin and 3-O-methyl-(+)-catechin to human volunteers the major urinary metabolites were shown to be the glucuronides of 3'-O-methyl-(+)-catechin respectively. Isolations from urine and from synthetic products have been carried out by semi-preparative high performance liquid chromatography; definitive elucidations of structures have been carried out by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.

Gas--liquid chromatographic determination of free dimethindene in human serum and urine at low concentrations.

A simple method for the determination of dimethindene down to a concentration of 10 ng/ml in human urine and serum is described. After the addition of an internal standard, the dimethindene is extracted as the free base with pentane. Measurements are made directly by gas--liquid chromatography using a flame ionization detector.