The Relationship Between Gene Polymorphisms Correlative With Drug Effect And Drug Responsiveness

Polymorphisms exist in human genomic DNA. And some polymorphisms such as metabolic enzymes, drug receptors, and some other genes correlated with diseases may affect the drug responsiveness. Some clinical phenomena can not be explained with traditional pharmacokinetcs and simultaneous modeling of pharmacokinetics and pharmacodynamics, such as with the same drug concentration in the body fluid, the responsiveness is far from the same. By investigation the relationship between gene polymorphisms correlative with drug effect and drug responsiveness, some complements may be made to the traditional theory of individualized strategy. Therefore, two common diseases, hypertension and asthma, were chosen. The relationships between drug responsiveness and polymorphisms of angiotensin Ⅱ type 1 receptor and β2-adrenoceptor were studied.Part Ⅰ: Influence of gene polymorphism of angiotensin II type 1 receptor on the antihypertensive responsiveness to angiotensin II type 1 antagonistFive variational positions have been found in angiotensin II type 1 receptor gene. The polymorphism of A1166→C was reported that it might be implicated in human essential hypertension, aortic stiffness and cardiac hypertrophy, so far, the genetic determinants of responsiveness to angiotensin II type 1 antagonists are unknown.Some 58 patients of mild to moderate essential hypertension were included in this study. These patients were treated with 80mg valsartan per day. At day 4th before valsartan was administered, a blood sample was extracted, the valley concentration of valsartan in the plasma was determined by HPLC. At day 7th, the blood pressure was measured. The genotype of AT1 was determined by PCR-RFLP.1Determination of valsartan in hypertensive plasma by HPLCThe valsartan plasma concentration in 43 AA homozygotes and 10 AC heterozygotes subjects were determined by HPLC. The retention time of valsartan was 12.5 min. The calibration curves were linear in the range of 5.9-2360 ng/ml. Theprecision values (RSD) of intra-day and inter-day were determined to be 2.83%~7.07% and 1.57%~8.41% respectively. The absolute recovery rate were 105.26%±4.64%. ①There is no statistic difference between the two groups(P＞0.05). The plasma concentration of valsartan in AA homozygotes was 155.63±81.12ng/ml, while in the AC heterozygotes group, the concentration was164.70±91.16ng/ml. ②The effect of age on the pharmacokinetics was great. The valley concentration of valsartan was higher in the elderly when compared with the young(178.38±92.22ng/ml Vs 139.93±71.64ng/ml, P＜0.05).2Influence of the polymorphism of AT1 on the responsiveness to AT1 antagonistGenomic DNA was extracted from peripheral blood by a modified phenol/chloroforms method. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to analyze the AT1 genotype.In all 58 hypertensions, the AA homozygotes gene frequency of AT1 was 82.8%, while the AC heterozygotes gene frequency was 17.2%, and the CC homozygotes was not found. And the A allele frequency was 91.4%, while the C allele was only 8.6%. The influence of the polymorphism of AT1 on the responsiveness to valsartan was analyzed in 27 subjects: 15 out of 22 AA homozygotes were effective, while in the AC heterozygotes group, 3 out of 5 were effective. There was no statistic difference of efficiency between the two groups. During the therapeutic period, the decline of the systolic pressure, diastolic pressure and pulse pressure of the AA homozygotes group was 2.85±2.50kPa, 1.77±1.58 kPa and 1.04±2.28 kPa. While in the AC heterozygotes groups, those figures were 4.52±4.37 kPa, 2.31±2.26 kPa and 2.21±2.83 kPa. Still the difference of decline of blood pressure between the two groups hadn't reached statistical level. From this study, we conclude that the A1166C polymorphism of AT1 receptor gene may not be the critical reason for the poor controllablity of blood pressure with AT1 antagonist for some patients.Part Ⅱ: Association between genetic polymorphi...