Background: Distribution of CYP2C9 and VKORC1 gene polymorphisms may vary significantly among different ethnic groups, and eventually influence the variation in drug metabolism or even failure.

As a membrane influx transporter, organic anion-transporting polypeptide 1B1 (OATP1B1) regulates the cellular uptake of a number of endogenous compounds and drugs. The aim of this study was to characterize the diversity of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene encoding this transporter in two ethnic groups populating the Western Balkans. The distribution of SCLO1B1 alleles was determined at seven variant sites (c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.1086C>T, c.1463G>C and c.*439T>G) in 266 Macedonians and 94 Albanians using the TaqMan allelic discrimination assay. No significant difference in the frequencies of the single nucleotide polymorphisms (SNPs) was observed between these populations. The frequency of the c.521T>C SNP was the lowest (<13.7 and 12.2%, respectively), while the frequencies of all other SNP alleles were above 40.0%. Variant alleles of c.1463G>C and c.1086 C>T SNPs were not identified in either ethnic group. The haplotype analysis revealed 20 and 21 different haplotypes in the Macedonian and Albanian population, respectively. The most common haplotype in both ethnic groups, *1J/*1K/*1L, had a frequency of 39.0% and 26.6%, respectively. In both populations, the variant alleles of the functionally significant c.521T>C and c.388A>G SNPs existed in one major haplotype (*15/*16/*17), with a frequency of 8.6 and 2.4% in the Macedonian and Albanian subjects, respectively. In conclusion, sequence variations of the SLCO1B1 gene in the studied populations occur at high frequencies, which are similar to that of the Caucasian population. Further studies are needed to evaluate the clinical significance of these SNPs and/ or the major SLCO1B1 haplotypes they form for a large number of substrates and for susceptibility to certain diseases.

The relative contribution of CYP2C9 allelic variants to the pharmacokinetics (PK) of ibuprofen (IBP) enantiomers has been studied extensively, but the potential clinical benefit of pharmacogenetically guided IBP treatment is not evident yet. The role of AKR1D1*36C>T (rs 1872930) allelic variant in interindividual variability of CYP450 mediated drug metabolism was recently elucidated. A total of 27 healthy male subjects, volunteers in IBP single-dose two-way cross-over bioequivalence studies were genotyped for CYP2C9*2, CYP2C9*3 and AKR1D1*36 polymorphisms. The correlation between CYP2C9 and AKR1D1 genetic profile and the PK parameters for S-(+) and R-(−)-IBP was evaluated. Remarkable changes in the PK values pointing to reduced CYP2C9 enzyme activity were detected only in the CYP2C9*2 allelic variant carriers. Statistically significant association between the AKR1D1*36 allele and the increased IBP metabolism (low AUC0-t and 0–∞, high Cltot and short tmax values for both enantiomers) was observed in subjects carrying the CYP2C9 *1/*3 or CYP2C9*1/*1 genotype. The clinical value of concomitant CYP2C9 and AKR1D1 genotyping has to be further verified.

Background: Inflammation´as measured by proinflammatory cytokines (interleukin [IL]-1´IL-6 and tumor necrosis factor α [TNFα])´is implicated in the development and maintenance of hypertension in patients1 and animal experimental models2-5. Salt loading as method for hypertension progression is extensively investigated in rats6-8. In this study we have studied the effect of salt loading on cytokine serum concentrations in SHR rats and evaluated possible immunomodulatory properties of valsartan and amlodipin monotherapy and combination. Materials and methods: 80 eight-week old SHR rats were used. Rats were divided into 2 groups: control group (SHRCń =16) given tab water ad libitum and a salt loaded group (n=64) in which tab water was replaced with NaCl solution (1%) given ad libitum for the complete course of the study. Salt loaded group after 12 weeks was divided in 3 treatment groups (SHRVal-valsartan as 10 mg/kg/ b. w.´SHRAmlo-amlodipin as 5 mg/kg/ b. w.´SHRVal/Amlo -5 mg/kg valsartan +2.5 mg/kg amlodipin per b. w.) and salt loaded control (SHRNaCl). After 12 weeks of drug treatment´serum TNFα´IL-1 and IL-6 concentrations were measured with commercially available enzyme-linked immunosorbent assay kits (Cusabio Biotech Co. Ltd) according to the manufacturer's instructions. In this study lipopolysaccharide (LPS) challenge was not used. Differences between certain time points and groups were analyzed with the Student's t-test for dependent and independent parameters´Kruskal Wallis ANOVA and Mann-Whitney U-test. Values of p <0.05 were considered to be statistically significant. Results: As shown in Table 1´by week 24 of the study´SHRNaCl presented higher IL-6´TNFα and IL-1 serum concentrations in comparison to SHRC group. Valsartan/amlodipin combination therapy effectively reduced IL-6 and TNFα serum concentrations in comparison to SHRNaCl group. There was no significant decrease in IL-1 concentrations in all drug treated groups in comparison to measured IL-1 concentrations in salt loaded control. Conclusions: Salt loading with NaCl solution (1%) in SHR rats for a period of 24 weeks had led to significant increase of measured proinflammatory cytokines. Valsartan and amlodipine effectively modulated IL-6 and TNFα levels. Drugs complementary mechanism had additive beneficial effect on proinflamatory cytokines.

Clarithromycin is a semi-synthetic macrolide antibiotic, chemically 6-0-methylerythromycin, formulated as immediate-release tablets, extended-release tablets, and granules for oral suspension. The objective of this study was to evaluate and compare the relative bioavailability, and therefore the bioequivalence of Clarithromycin 500 mg test formulation versus a reference Klacid® forte 500 mg formulation, following a single dose administration under fasting conditions. The study was a single center, open, single dose, randomized, two-way crossover study in healthy male volunteers, with a wash-out period of one week between study periods. Twenty-four male healthy volunteers, aged 18-49 years were included into study. Blood samples for determination of clarithromycin and 14-OH clarithromycin concentrations were withdrawn at zero (pre-drug administration), 0.33, 0.66, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24 and 36 hours post-drug administration. The determination of clarithromycin and 14-OH clarithromycin concentrations in plasma was performed using validated LC/MS/MS method and internal standardization after liquid/liquid extraction with methyl t-butyl ether. The test formulation of clarithromycin, dosed at 500 mg is bioequivalent for primary clarithromycin and 14-OH clarithromycin parameters (Cmax, AUC0-t and AUC0-∞) to the reference formulation after a single oral administration of 500 mg clarithromycin. Both medications were well tolerated with no serious adverse events. Thus, in view of the clinical use, both formulations are exchangeable without restrictions. Keywords: clarithromycin, 14-OH clarithromycin, bioavailability, bioequivalence study, single-dose