Quantitative thin-layer chromatographic method for the determination of procainamide and its major metabolite in plasma

A sensitive and accurate spectrodensitometric method was developed for the determination of procainamide and its major metabolite, N-acetylprocainamide, in plasma. The method involves extraction into organic solvent at alkaline pH, separation by thin-layer chromatography and direct measurement of the adsorbance of the compounds on the plate at 275 nm. Quantities as low as 10 ng could be measured and a linear relationship was obtained between peak areas and amounts of the compounds in the spots from 10 to 200 ng. The recovery of both drugs from plasma was from 95.4 to 104.8%. The method is sensitive and specific, and procainamide was well separated from N-acetylprocainamide at all investigated concentrations. The method is recommended for clinical assays and pharmacokinetics studies.     

Importance of acetylator phenotype in the identity of Asian populations

The Marma, Tripura, and Chakma are tribal populations of South Asian countries such as Bangladesh. The populations are thought to be immigrants who started moving from their original home in the Far East toward the west and south. We randomly selected 80 Marma, 53 Tripura, and 43 Chakma to determine acetylation capacity and acetylator phenotype. The mean acetylation capacities were 63% in the Marma, 65% in the Tripura, and 70% in the Chakma. The acetylator phenotype was bimodally distributed as fast and slow acetylator. The frequencies of fast acetylator were 83% in the Marma, 89% in the Tripura, and 88% in the Chakma. According to acetylation capacity, the tribes are different from the founder nontribal populations of Bangladesh. They identify themselves as having a separate single population origin. The frequency of fast acetylator predicted served as the acetylator status of the Far East Asian population. The segregation of populations by acetylator phenotype on geographic longitude might be appropriate for geonational identification of Asian populations.     

Verification of therapeutic levels of procainamide and N-acetyl- procainamide in ventricular arrhythmia]

Therapeutical efficacy was clinically evaluated in 21 patients with ventricular cardiac arrhythmias. The drug was given orally with preceded intramuscular dose. Therapeutic effect was verified by the measurements of procainamide and N-acetylprocainamide concentrations in blood serum to determine the minimal effective concentration of the drug required to obtain satisfactory antiarrhythmic effect. Procainamide proved effective in cardiac arrhythmias in 14 patients (66.7%) with statistical significance in the acute myocardial infarctions; blood serum procainamide plus N-acetylprocainamide levels being were below the therapeutical range. The poor correlation of the dose of the drug and respective procainamide, N-acetylprocainamide concentrations in blood was observed. Relationship of the therapeutical effects blood serum level of the drug should be estimated basing of the assays of both procainamide and N-acetylprocainamide .     

Effect of rifampin, phenobarbital pretreatment, and acetylator phenotype on acetylisoniazid metabolism in the rabbit

The metabolism of [14C]acetylisoniazid was studied in male New Zealand White rabbits. Pretreatment of the rabbits with the microsomal enzyme inducers rifampin and phenobarbital had little effect on acetylisoniazid metabolism. Rifampin appears to produce some inhibition of acetylation of the metabolite acetylhydrazine to diacetylhydrazine. Acetylation phenotype was an important factor. Covalent binding of 14C to hepatic protein increased as the acetylation rate decreased. In plasma and urine acetylhydrazine levels were negatively correlated with acetylation rate and diacetylhydrazine levels were positively correlated as one would expect. It was concluded that in the rabbit covalent binding to hepatic protein was more dependent on the acetylation rate than on induction of microsomal oxidase.     

Biokinetics of a new prodrug gidazepam and its metabolite]

Pharmacodynamics and pharmacokinetics of a novel tranquilizing agent--gidazepam (I), a prodrug, and its physiologically active metabolite--7-bromo-5-phenyl-1,2-di-hydro-3H-1,4- benzodiazepine-2-one (II) in mice organism were studied. The form of relationship was determined between the dynamics of the anticonvulsant effect of labelled (2-14C-) I and II and the kinetics of the content of 14C-compounds in the experimental animals brain. It was noted that the biophase of the effect and the effector fragment of the scheme of biokinetics for I and II are identical. The effector prognosis of pharmacokinetics of I was realized. The comparison of the main characteristics of biokinetics for the prodrug (I) and drug (II) allowed us to reveal the nature of the quantitative differences of these pharmacological effects.     

High frequency of the rapid isoniazid acetylator phenotype in Lagos (Nigeria)

The metabolism of isoniazid was investigated in 323 unrelated and healthy Nigerians in Lagos using a simple dosage and urinalysis procedure. The distribution was bimodal and the population frequency of rapid acetylators was 61.92%, a value higher than that for most Caucasian populations. Males and females were equally affected by the traits. Analysis of both the population and pedigree data showed that the slow acetylator phenotype is a recessive trait, and the gene frequency of the recessive allele as computed by maximum likelihood methods is 0.6175 +/- 0.022. The clinical implications of these findings are discussed.     

Biochemical differences in Cannabis sativa L. depending on sexual phenotype

Hemp (Cannabis sativa L.) is a species considered as having one of the most complicated mechanisms of sex determination. Peroxidase and esterase isoenzymes in leaves of the two sexual phenotypes of hemp were studied. Significant differences in isoperoxidase and isoesterase patterns were found between male and female plants, both in the number and stain intensity of bands. For both esterase and peroxidase, the isoenzymatic spectrum is richer for staminate plants. Also, some differences are obvious between the two sexes concerning catalase and peroxidase activities, as well as the level of soluble protein. The quantitative analysis of flavones, polyholozides and polyphenols emphasized differences depending not only on sex, but also on tested organ.     

Pharmacokinetics and tissue distribution of enrofloxacin and its metabolite ciprofloxacin in the Chinese mitten-handed crab, Eriocheir sinensis

The pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin were investigated in the Chinese mitten-handed crab after a single intramuscular injection of enrofloxacin at 5.0mg/kg body weight. The tissue concentrations of enrofloxacin and ciprofloxacin were determined simultaneously by a high-performance liquid chromatography (HPLC) method. The data were analyzed with Practical Pharmacokinetic Program 3P97. The highest average concentrations of enrofloxacin in liver, muscle, gill, and hemolymph were 3.93, 12.42, 16.73, and 11.04 microg/g (ml), respectively. The elimination half-lives (t(1/2beta)) for enrofloxacin were 92.42, 64.86, 38.80, and 52.39 h, respectively. The AUC(0-infinity) values for enrofloxacin were 304.80, 260.74, 288.30, and 269.24 microg h/ml, respectively. Ciprofloxacin could be detected in all four tissues. The respective values of main pharmacokinetics parameters Cmax, t(1/2beta), and AUC(0-infinity) were 0.52 microg/g (ml), 38.38 h, and 35.06 microg h/ml for liver; 0.24 microg/g (ml), 65.36 h, and 25.64 microg h/ml for muscle; 0.10 microg/g (ml), 112.88 h, and 11.57 microg h/ml for gill; and 0.30 microg/g (ml), 93.33 h, and 39.99 microg h/ml for hemolymph.     

An analysis of the ionic regulation of the specific binding of 3H-diazepam depending on the phenotype of the emotional stress reaction]

It was shown that low NaCl concentrations (less than 50 mM) had more pronounced stimulatory effect on [3H]-diazepam ([3H]-DZ) binding in brain membranes of Balb/c (C) mice than in C57B1/6 (B6) mice. These interstrain differences disappeared after emotional stress in "open field" (OF) test. Low doses of diazepam (0.75 mg/kg) and hydazepam (1 mg/kg) induced anxiolytic effect in C mice and restored their normal [3H]-DZ binding level in the presence of NaCl. On the opposite, effects of the same doses of the benzodiazepines were not revealed either on the behavior in OF test or on stimulating properties of NaCl in B6 mice. Both benzodiazepines (10 mg/kg) induced similar behavior (sedative) and receptor (decrease of NaCl stimulating ability) in B6 and C mice. We made a conclusion that the ability of NaCl to increase [3H]-DZ binding is a physiological index which reflects hereditary differences in emotional-stress reactions and behavioral effects of benzodiazepine tranquillizers.     

Pharmacokinetics of the enantiomers of trans-tramadol and its active metabolite, trans-O-demethyltramadol, in healthy male and female chinese volunteers

By using a high-performance capillary electrophoresis method, the pharmacokinetics of the enantiomers of trans-tramadol (trans-T) and its active metabolite, trans-O-demethyltramadol (M1), was studied in healthy male and female Chinese volunteers after oral administration of 100 mg trans-T hydrochloride. The values of Cmax for the enantiomers of trans-T and M1, and AUC0- infinity for (-)-trans T, (+)-M1, and (-)-M1 were higher in females than in males. The values of V(d)/F for the enantiomers of trans-T and CLr for (+)-M1 were lower in females than in males. The value of t(1/2) for (-)-M1 was longer in females than in males. There were significant differences in pharmacokinetic parameters of the two enantiomers of trans-T or M1 both in males and in females. The (+)/(-)-enantiomeric ratios of t(max), V(d)/F for trans-T in males were significantly different from those in females and the (+)/(-)-enantiomeric ratios of pharmacokinetic parameters for M1 in males were similar to those in females. There are gender-related differences in the pharmacokinetics of the enantiomers of trans-T and M1 which may be due to the greater body weights for men and/or the higher CYP2D6 activity in women. The pharmacokinetics of trans-T and M1 is stereoselective in men and women. There is a gender-related difference in the stereoselectivity in pharmacokinetics of trans-T in human and the stereoselectivity in pharmacokinetics of M1 in men is similar to that in women. Chirality 16:112-118, 2004.     

Characterization of human lymphocyte N-acetyltransferase and its relationship to the isoniazid acetylator polymorphism

Characterization of human lymphocyte N-acetyltransferase (NAT) for specific activity, substrate specificity, inhibition, pH optimum, apparent K_m, kinetic mechanism, trypsin stability, freezing stability, and heat stability was carried out in rapid and slow isoniazid (INH) acetylators. There is a statistically significant difference in the heat stability of lymphocyte NAT from rapid and slow INH phenotypes. The lymphocyte enzyme from rapid INH acetylators is less heat stable than the lymphocyte enzyme from slow INH acetylators. This is an indication of a structural, possibly polymorphic, difference in lymphocyte NAT from the two acetylator phenotypes.     

Specificity of tyrosine metabolism depending on the state of melaninogenesis]

The excretion of metabolites of tyrosine (p-hydroxypyruvic acid-p-HPA, homogentisinic acid-HGA, total keto acids-TKA) and the activity of tyrosine aminotransferase of the tissues of 36 albino and 36 black rabbits was measured. The initial level of tyrosine metabolites in the urine of black and albino rabbits differed but little from one another. With the introduction of L-tyrosine, the quantity of the excreted p-HPA increased sharply, and of the HGA decreased in the albino rabbits. Among black rabbits an increase of the HGA excretion with a comparatively stable level of the excreted p-HPA was noted. Among all the tissues investigated only in the skin and the liver of albino rabbits there was a sharp increase in the initial tyrosine aminotransferase activity after the feeding of L-tyrosine, which testified to a probable adaptive synthesis of the enzyme. Analysis of the data obtained showed that tyrosine metabolism probably depended on the state of melaninogenesis.