P327 Interaction of pitavastatin with grapefruit juice in subjects with different efflux transporter BCRP ABCG2 421C>A genotypes

Posters / International Journal of Cardiology 125 Suppl. 1 (2008) S51–S73 P327 Interaction of pitavastatin with grapefruit juice in subjects with different efflux transporter BCRP ABCG2 421C>A genotypes V.W.L. Mak1 *, M. Hu1 , O.Q.P. Yin2 , M.S.S. Chow2 , B. Tomlinson1 . 1 Department of Medicine and Therapeutics and 2 School of Pharmacy, The Chinese University of Hong Kong, Hong Kong SAR, China Objectives: Pitavastatin, a novel HMG-CoA reductase inhibitor, is excreted into bile through transporters including the breast cancer resistance protein (BCRP, gene ABCG2), which may also limit intestinal absorption. The C421A polymorphism in ABCG2 is associated with reduced protein expression and is common in Chinese populations. We investigated the effect of this polymorphism on the pharmacokinetics of pitavastatin and its lactone and the possible interaction with grapefruit juice. Methods: Twelve healthy male Hong Kong Chinese volunteers were genotyped for the ABCG2 C421A polymorphism (5 homozygous 421CC, 5 heterozygous 421CA, 2 homozygous 421AA) and took pitavastatin 2 mg with 200 ml of water or 200 ml double-strength grapefruit juice on separate occasions. Plasma concentrations of pitavastatin acid and the lactone metabolite were measured over 48 hours. Results: For both pitavastatin acid and lactone the maximum plasma concentration (Cmax ) was about 10% lower and area under the plasma concentration–time curve (AUC) values were about 10% higher (all P < 0.05 except Cmax with acid) with grapefruit juice than with water. Subjects with at least one 421A allele had lower values for Cmax and AUC for pitavastatin acid and lactone (P < 0.05 for lactone AUC0−∞ 421CA/AA 188.3±24.2 vs. 421CC 258.8±59.6 ng·h/ml). The effects of grapefruit juice on AUC tended to be greater in subjects with the 421CC genotype than those with one 421A allele. Conclusion: Grapefruit juice appeared to increase the bioavailability of pitavastatin slightly, whereas having the 421A allele was associated with slightly lower AUC values. The effects of grapefruit juice tended to be greater in subjects with the 421CC genotype. All these effects were small and are unlikely to influence the efficacy or safety of pitavastatin. P328 Condition of immune system in patients with non-rheumatic myocarditis G. Nagaeva *, T. Abdullaev. The Republican Specialized Center of the Cardiology, Tashkent, Uzbekistan Aim: To estimate a degree of immunologic shifts at patients with nonrheumatic myocarditis (M). Materials and Methods: Clinical survey, the immunologic status of blood, record of electrocardiogram, an echocardiography. 64 patients are surveyed: 35 women and 29 men, middle age 35.34±1.16 (from 20 up to 54). Results and Discussion: Analysis of the received results has shown, that all markers of immunity at sick M were below, than middle parameters on a population as a whole, thus the majority of them had authentic character (Table 1). As is known, T-lymphocytes-supressors, (CD8), suppress ability of lymphocytes to participate in development of antibodies and thus provide immunologic tolerance. Our results have shown, that at sick M fraction CD8 is kept high, concerning fraction CD4, that, possibly, suppresses function T-helpers in the induction humoral immunity. Results received by us have shown hygh authentic a low level B-lymphocytes at patients with M. The patients with M, practically, do not have increase of fraction Ig G, being the basic serumal immunoglobulin responsible for process of humoral protection of an organism. During too time our patients differed hygh authentic augmentation of level Ig A, that confirms presence of inflammatory process at patients surveyed by us. Conclusion: Thus, on the basis of the above-stated it is possible to draw a conclusion, that at patients with not rheumatic myocardites mark depression both cellular, and a humoral part of immunity, i.e. as a whole, the myocarditis is accompanied by development of an immunodepression.

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Table 1. Markers

T-lymphocytes, % T-helpers (CD4), % T-supressors (CD8), % CD4/CD8 B-lymphocytes, % CD16 Ig G, mg% Ig A, mg% Ig M, mg%

Values (M±m) Average normal population

Patients with MT (n = 64)

62.14±1.64 37.29±0.81 19.86±0.67 1.82±0.051 28.71±1.229 8.714±0.68 1242±77.14 134±4.995 140.7±11.19

51.17±1.39** 25.95±0.83** 19.85±0.61 1.34±0.04** 17.05±0.61** 17.28±0.47** 1272.8±33.62 164.9±4.53 ** 125.6±3.33

**P < 0.001 at comparison with average specifications on a population.

P329 The heart rate variability in patients with non-coronaries diseases G. Nagaeva *, T. Abdullaev, R. Kurbanov. The Republican Specialized Center of the Cardiology, Tashkent, Uzbekistan Aim: The comparative estimation of parameters of the heart rate variability (HRV) in patients with idiopathic dilated cardiomyopathy (DCM) and not rheumatic myocarditis. Materials and Methods: 32 patients are included in research, from them 17 with DCM (I group) and 15 with myocardites (II group). Middle age of patients DCM = 46.94±4.82 years; myocardites = 33.2±4.53 years. The heart failure (HF) was estimated on a functional class (FC), according to diagnostic criteria NYHA, 29.41% were in NYHA II; in NYHA III – at 52.94% and in NYHA IV – at 17.65% patients; in II group – in NYHA I was marked at 20%, in NYHA II – at 60% and in NYHA III – at 20% patients. In the control period of inspection spent registration of an electrocardiogram and daily monitoring of an electrocardiogram with an estimation of parameters HRV. Results and Discussion: By results of research it is established, that at patients the I-th group the heart rate (HR) as during active time of day, and at night remained considerably above, than with patients of II group (92.65±3.86 and 79.71±2.374; 80.93±2.81 and 66.5±3.07 accordingly I and II groups during night and day). The estimation of circadian changes at these groups of patients also has taped, though also doubtful, but depression of an analyzed index at patients DCM (1.159±0.027), than at patients myocardites (1.238±0.065). Time parameters HRV at patients DCM were is significant below: SDNN = 94.76±15.24; SDANN = 72.06±10.19; rMSSD = 49.47±14.18 and pNN50 = 12.88±5.83% in comparison with similar parameters of patients myocardites (SDNN = 150.3±22.29; SDANN = 126.9±19.06 (both P < 0.05); rMSSD = 70.13±22.08; pNN50 = 13.33±3.15%). At the analysis of spectral parameters HRV power in range LF essentially did not differ, also as well as power in range HF, however the normalized power in range LF in group of patients DCM was on 14.1% below, than at patients with myocardites whereas the normalized power in range HF at patients DCM on the contrary has appeared above on 31.36%. Attitude LF/HF at patients the I-th group was on 13.73% below, than in the II group, but as a whole on both groups the prevailation of low-frequency spectrum HRV above high-frequency is marked. Conclusions: 1. At patients with non coronaries diseases of myocardium observe disturbance of a neurovegetative regulation of chronotropic function of heart. 2. At patients DCM a degree of disturbance of a vagosympathetic regulation of activity of cardiovascular system in 1.5 and more times it is expressed compared with group of patients with myocardites.