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A ,,sine qua non" requirement for a generic formulation to be admitted for a medical use is to provide bioavailability studies in healthy subjects. Therefore, those studies were performed for 150 mg moclobemide tablets (Jelfa, Poland) versus 150 mg Aurorix (Hoffmann la Roche) reference tablets. An open-label, two-phase crossover study was conducted with 10 healthy subjects. Pharmacokinetic parameters (AUC, ke, t1/2, Cmax, tmax, tlag, V/f, Cl/f) obtained at the same time for moclobemide were supposed to be confronted with the literature data available for healthy volunteers. The plasma moclobemide levels as a function of time were calculated according to either an open one-compartment body model with lag time of absorption or non-compartmental method for calculation of bioavailability using Phoenix WinNonlin 8.0 software. For those reasons a suitable HPLC method was worked out. Carbamazepine was proposed as an internal standard and ammonia as well as Na2HPO4 as alkalizing agents for the mobile phase and the liquid-liquid extraction of moclobemide from human blood plasma, respectively. Basic pharmacokinetic parameters of moclobemide obtained in the paper are essentially equal to the literature data for the healthy subjects. However, bioavailability parameters (AUC0→t, AUC0→∞, Cmax, tmax) were greater for moclobemide tablets (Jelfa) if compared to Aurorix tablets (Roche) by more than 20 %. Furthermore, the extent of bioavailability (110.6 %) for the generic moclobemide tablets if compared to Aurorix tablets is not significantly different. It seems to us that the number of subjects should be increased from 10 to 24 to help to clarify that inconsequence.

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Bioavailability studies were performed for 50 mg propylthiouracil tablets (Jelfa, Poland) versus 50 mg propycil tablets (Solvay, Germany). An open-label, two-phase, crossover study was conducted with 15 healthy subjects. All subjects were randomly assigned a drug assignment number from I to XV, which was used throughout the experimental period. Dosing periods for both formulation tablets: Propylthiouracil, Jelfa vs. Propycil, Solvay were separated by at least 7 days washout period. Following single dose drug administration, venous blood samples were obtained at the required times for 12 h and the drug serum levels were determined by HPLC and used for PK analysis. PK parameters were calculated by the computer program TopFit 2.0. HPLC chromatograms show retention times for propylthiouracil and methylthiouracil (internal standard) of 5.97 and 2.75 min, respectively at 20 °C, providing adequate separation from each other and from endogenous serum components. Pharmacokinetic parameters for both tablets were not significantly different. Serum concentration-time profiles are superimposed for the above tablets according to an open one-compartment body model. EBA for Propythiouracil Jelfa tablets vs. Propycil tablets was 96.8%, and not significantly different. Some authors applied a two-compartment body model for the calculation of propylthiouracil pharmacokinetic parameters, which approach is not rational according to our data.

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WHAT IS KNOWN AND OBJECTIVE: The reasons of clopidogrel (CLP) resistance are still unclear. The response to CLP may be influenced by both genetic and non-genetic factors. Among genetic factors, common polymorphisms in the gene coding glycoprotein-P (P-gp, MDR1 and ABCB1) are considered as potential determinants of the efficacy of CLP treatment. The aim of this study was to evaluate the influence of ABCB1 3435C>T genetic polymorphism on the pharmacokinetics and pharmacodynamics of CLP and its metabolites: diastereoisomers of thiol metabolite (the inactive H3 and the active H4) and inactive carboxylic derivative. METHODS: The study group included 42 patients undergoing elective coronary angiography and percutaneous coronary intervention. The plasma concentrations of CLP and its metabolites were measured by a validated HPLC-MS/MS method. Whole-blood aggregation was determined with Multiplate analyzer. For evaluation of ABCB1 3435C>T polymorphism, PCR-RFLP method was applied. RESULTS AND DISCUSSION: It was found that Exposition to the unchanged CLP, measured by AUC0-t of the drug, was significantly lower (P = 0·012) in TT homozygotes comparing to that observed in CC and CT genotypes, although no correlation was found between platelet aggregation and ABCB1 genetic polymorphism. WHAT IS NEW AND CONCLUSION: Our findings show that the presence of 3435C>T allele has an impact on CLP pharmacokinetics but not on the drug pharmacodynamics. Therefore, the 3435C>T genotype may not be the primary determinant influencing the pharmacokinetics of the active H4 metabolite and antiplatelet effect of the drug.

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11ß-Hydroxysteroid dehydrogenase type 2 (11ß-HSD2) catalyzes the inactivation of cortisol (F) to cortisone (E) in aldosterone target tissues, thereby protects mineralocorticoid receptor from F. Failure of 11ß-HSD2 function is the basis of apparent mineralocorticoid excess, and its mild disturbances are suggested to lead to hypertension. The aim of the study was to analyze the 11ß-HSD2 activity in hypertensives and healthy volunteers. Glucocorticoids (GCs) profile was estimated to verify whether the disorders of GCs balance may be involved in essential hypertension etiology. Exons and short introns of HSD11B2 were sequenced to evaluate existing mutations and their potential implications in the disease. The identified polymorphisms were assessed in case-control study to determine their relevance to hypertension. No significant differences in values of plasma F/E and UFF/UFE (urinary free F to free E) were observed between hypertensives and controls. The value of (THF+allo-THF)/(THE+allo-THE) (urinary tetrahydro-metabolites of F to tetrahydro-metabolites of E) in hypertensives was higher than in normotensives. Logistic regression demonstrated that the increase of one unit of (THF+allo-THF)/(THE+allo-THE) value increases the risk of hypertension over 11-fold. Genotyping indicated no hypertension related mutations in the coding region and short introns of HSD11B2.

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The pharmacokinetics of ibuprofen enantiomers and its chiral metabolites, namely (R,S)-29-hydroxyibuprofen and (RR,RS,SR,SS)-29-carboxyibuprofen, was studied in healthy volunteers carrying different alleles coding cytochrome P450 (CYP) 4502C isoenzymes. Following administration of 400 mg of racemic ibuprofen, enantiomers of the parent compound and their metabolites were isolated from plasma and urine samples using solid-phase extraction and were quantified by the validated capillary zone electrophoresis method. The levels of the analytes in biological fluids were used to calculate their pharmacokinetic parameters in subjects with different variants of CYP2C8 and CYP2C9 isoenzymes. The analysis of each subject's genotype was carried out using polymerase chain reaction-restriction fragment length polymorphism. Impaired metabolism of ibuprofen enantiomers was associated with the presence of CYP2C8*3, CYP2C9*2 and CYP2C9*3 alleles. The greatest effect of mutated alleles on pharmacokinetics was observed in a subject with a CYP2C8*1/*3, CYP2C9*1/*2 genotype. This subject appeared to have lower value of clearance, greater area under the curve (AUC) and longer time t(0.5) in comparison with the wild-type.

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Pharmacokinetic studies of high-dose treosulfan were carried out in seven paediatric patients (age range: 2-15 years) undergoing treosulfan-based conditioning regimen prior to allogeneic haematopoietic SCT. Treosulfan was administered intravenously in a daily dose of 10, 12 or 14 g/m(2) within 2 h. Five out of seven patients received 12 g/m(2). The plasma concentrations of treosulfan and its quantity eliminated with urine were determined using a validated HPLC method with refractometric detection. Pharmacokinetic parameters were evaluated following first dose using a two-compartment disposition model. These studies demonstrated a dose-dependent increase of area under the concentration (AUC) and maximum concentrationplasma (C(max)), but there was variability of these parameters. Rapid clearance of tresoulfan was observed, especially in 10 and 12 g/m(2) doses. Terminal half-life (t(0.5)) of treosulfan was in the range of 1.71-2.15 h, but the mean percent of parent drug eliminated with urine was 30%, range 16.3-45.4% of the total dose eliminated during the first 12 h after administration. The results of this study confirmed the linear pharmacokinetics of treosulfan, as used in children. However, variability of pharmacokinetic results observed in children studied demonstrates the need for pharmacokinetic evaluation in each paediatric patient undergoing the treosulfan-based preparative regimen, including those using different doses. This approach could enable further reduction of the risk of early and late organ toxicity related to high-dose treosulfan in paediatric patients.

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Steady-state pharmacokinetics of indobufen (INDB) enantiomers administered as racemic INDB (rac-INDB) tablets and bleeding time were studied in patients. Two-hundred mg INDB tablets (Ibustrin) were administered twice daily for 7 days to obliterative atherosclerosis patients. Enantiospecific reversed phase (RP) HPLC with UV detection (lambda = 275 nm) was used for determination of INDB enantiomers in serum of patients. The ratio AUCR:AUCS equalled 1.7 +/- 0.2 as a result of higher (-)-R-enantiomer serum levels. The (+)-S-enantiomer was more rapidly eliminated (oral clearance, Cl = 1.1 +/- 0.3 L/h) than its (-)-R-antipode (Cl = 0.7 +/- 0.2 L/h). Therefore, the mean steady/state levels of (-)/R/enantiomer (13.5 +/- 3.8 mg/L) exceeded those of its (+)-S-enantiomer (7.8 +/- 1.8 mg/L). Furthermore, half-life (t1/2) was significantly shorter for (+)-S-INDB (t1/2 = 4.5 +/- 1.2 h as compared to (-)-R-INDB (t1/2 = 7.4 +/- 2.4 h). However, no significant differences were observed in the respective Vd values. The bleeding time of patients was not significantly extended. The above pharmacokinetic data provide a rationale for potential future replacement of INDB racemic tablets with tablets of its (+)-S-enantiomer.

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Studies were performed on the effect of ibuprofen racemate ionisation extent on the pharmacokinetics of its enantiomers following administration in suppositories to rabbits. The suppositories, containing 146.3 mg ibuprofen in acidic form (IBP) or 250 mg ibuprofen lysinate (IBPL), equivalent to the above IBP dose, were prepared using lipophilic Witepsol H-15 as a base and administered to rabbits in a crossover design. Compared with IBP, administration of IBPL was followed by faster absorption and elimination of R and S enantiomers. However, significant differences at alpha=0.05 were observed only at the stage of elimination. AUC was markedly higher following administration of suppositories containing IBP than following suppositories with IBPL and this pertained to both R and S enantiomers. Evident inversion of R into S form was noted 30 min following IBPL administration and 1 h after IBP administration. Ionisation extent only insignificantly affected the scope of chiral inversion of ibuprofen R into S form (AUC(S-IBP)/AUC(R-IBP)=1.66, AUC(S-IBPL)/AUC(R-IBPL)=1.57). No presystemic inversion of R into S was observed in rabbits following administration of IBP or IBPL in suppositories. IBP enantiomers were isolated from 0.5 ml serum using solid phase extraction in C(18) columns and were quantified by HPLC using the chiral Whelk O1 column and UV detector (lambda=264 nm).

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A rapid and selective liquid chromatography (LC) with solid phase extraction (SPE) to quantify indobufen (INDB) enantiomers is described. The INDB enantiomers and internal standard (racemic flurbiprofen) are extracted from a small volume of acidified serum (0.2 ml) by means of SPE using cartridges with octadecyl chemically bound phase and analysed on reversed phase (RP), C18 column with ultraviolet detection at 275 nm. Recovery of both INDB enantiomers was in the range 92.1-94.3%. The mobile phase is composed of acetonitrile-potassium dihydrogen phosphate (pH 4.75; 10 mM) (38:62, v/v). The linear range of the standards curves was from 0.25 to 25.00 microg ml(-1) in serum for both enantiomers. The limit of quantification and detection for both INDB enantiomers in serum were 0.25 microg ml(-1) (CV < or = 10%), and 0.1 microg ml(-1), respectively. Both intra- and inter-day accuracy and precision of the calibration curves were determined and their CV values did not exceed 10%. The validated method has been successfully applied for chiral pharmacokinetics studies of INDB from tablets and intramuscular injections in man.

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The influence of administration route (oral or intramuscular (i.m.)) on the pharmacokinetics of total indobufen (INDB) enantiomers was studied in healthy volunteers after a 200 mg dose as a single oral tablet or i.m. injection. Enantiospecific reversed phase (RP) HPLC with UV detection was used for the determination of INDB enantiomers in serum. INDB enantiomers were isolated from serum by solid phase extraction (SPE) procedure using C(18) columns. INDB enantiomers were converted to their L-leucinamide diastereoisomers and separated on a C(18) HPLC column. INDB from i.m. injections is absorbed faster (t(max) = 0.6-0.9 h) than from tablets (t(max) = 1.3-1.8 h). The area under curve (AUC) after administration of the tablet was slightly higher than after i.m. injection. The pharmacokinetic behaviour of (+)-S- and (-)-R-INDB after administration of the tablet was different from i.m. injection of racemic INDB. The (+)-S-enantiomer is more rapidly eliminated than its (-)-R-antipode. Statistically significant differences also occurred between enantiomers in AUC, first order elimination rate constant (k), clearance (Cl). The ratio AUC(R):AUC(S) was similar for the tablet (1.57-1.62) and i.m. injection (1.59-1.62). It was concluded that the formulation and extent of ionisation of rac-INDB (acid or sodium salt of INDB) do not significantly influence its stereoselective pharmacokinetics.

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Ibuprofen (IBP) was used to demonstrate that freshly isolated rat hepatocytes offer a suitable model to investigate the oxidative metabolism of antiinflammatory 2-arylpropionic acids (profens). The formation of two major oxidative metabolites of IBP (metabolite A--hydroxyibuprofen and metabolite B--carboxyibuprofen) was observed with the use of rat hepatocytes. The incubation of ibuprofen with a suspension of rat hepatocytes in Hanks' buffer during 60 min. resulted in a decrease of racemic IBP and both R(-)-IBP and S(+)-IBP concentration coincided with the appearance of its major racemic metabolites (metabolite A and metabolite B). The relative abundance of the above IBP metabolites produced by hepatocytes was consistent with their quantitative profiles in vivo in rat. The results confirm the value of isolated hepatocytes as a predictive model for the in vivo metabolism pattern of profens.

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Concentration of ibuprofen in rabbit blood was found to be considerably higher after application of Imbun-500 suppositories, containing 500 mg of ibuprofen lysine salt equivalent to 292.6 mg of free ibuprofen, than after application of ibuprofen dragees containing 400 mg of the free drug. Parameters characterizing biological availability of ibuprofen in Imbun-500 suppositories (AUC, Cmax, tmax) were determined. Ibuprofen lysine salt proved to be considerably more easily absorbed from suppositories than ibuprofen from dragees of either home or foreign production.

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