人参皂苷Rb1抑制β淀粉样蛋白25-35诱导的皮层神经元tau蛋白过度磷酸化

目的探讨人参皂苷Rb1对凝聚态β-AP_25-35诱导的胎鼠皮层神经元tau蛋白过度磷酸化的影响及其可能的作用机制。方法通过蛋白免疫印迹法和免疫细胞化学染色法检测神经元tau蛋白磷酸化水平、总tau蛋白水平和糖原合成酶3β(GSK-3β)的蛋白表达水平。结果凝聚态β-AP_25-35(20 μmol·L^-1)作用于皮层神经元12 h，tau蛋白磷酸化水平和总tau蛋白水平均增高，同时GSK-3β蛋白表达也增多。用人参皂苷Rb1或GSK-3β特异性抑制剂氯化锂预处理后，凝聚态β-AP_25-35诱导的tau蛋白的过度磷酸化受到明显抑制，同时GSK-3β的表达也降低。结论人参皂苷Rb1可通过抑制GSK-3β的表达来抑制凝聚态β-AP_25-35诱导的皮层神经元tau蛋白的过度磷酸化。     

三七皂苷中人参皂苷Rg1与Rb1口服吸收及其体内药代动力学的研究和比较

分别考察三七总皂苷(PNS)在大鼠灌胃和静脉给药后的人参皂苷Rg₁(Rg₁)、人参皂苷Rb₁(Rb₁)的胆汁排泄；采用平衡透析法测定药物的血浆蛋白结合率；并结合药代动力学的实验结果，研究和比较Rg₁与Rb₁的口服吸收及其体内药代动力学性质。结果表明，静脉给药后10 h，Rg₁及Rb₁胆汁排泄累积量分别为给药剂量的(61.48±18.30)%和(3.94±1.49)%；灌胃给药后12 h，Rg₁及Rb₁胆汁排泄累积量分别为给药剂量的(0.91±0.51)%和(0.055±0.02)%。Rg₁及Rb₁的血浆蛋白结合率分别为6.56%～12.74%和80.11%～89.69%。Rg₁的胃、肠和肝的通过率(F_S，F_I和F_H)分别为49.85%，13.05%和50.56%；Rb₁分别为25.82%，4.18%和65.77%。因此，肠壁吸收差是Rg₁和Rb₁生物利用度低的主要原因。Rg₁具有较高的胆汁排泄和较低的血浆蛋白结合率，Rb₁的胆汁排泄较低，而血浆蛋白结合率较高。Rb₁的肠黏膜透过性和体内消除速度都低于Rg₁，但前者的平均滞留时间(MRT)和血药浓度曲线下面积(AUC)均大于后者。     

极谱法研究辅酶Q10与β-环糊精的包结行为

目的研究辅酶Q_{10与β-环糊精(β-CD)的包结行为。方法用极谱法考察主体分子β-CD与电活性客体分子辅酶Q10发生包结反应时，包结物还原波峰电流随时间的变化，峰电位随β-CD浓度的变化，并在自然光照条件下分别考察辅酶Q10和包结物的还原波峰电流随时间的变化。结果在0.1 mol·L^-1 HAc/NaAc (pH 4.7)的乙醇-水(60∶40)介质中，辅酶Q10与β-CD形成1∶1的包结物，测得其包结常数kf为1.26×10⁴ L·mol^-1，包结反应的表观速率常数k为6.64×10^-2 min^-1。并测得辅酶Q10的光降解表观速率常数k为7.77×10^-3 min^-1，辅酶Q10-β-CD包结物的k为3.38×10^-3 min^-1。结论辅酶Q10和β-CD可形成包结物，并在一定程度上提高了辅酶Q10的光稳定性。}     

三七绒根中皂甙B1及B2的分离和鉴定

从三七Panax notoginseng(Burk.)F.H.Chen绒根中分得二种微量皂甙,三七皂甙B₁和B₂三七皂甙B₁为一种新皂甙,证明其结构为达玛20(22)-烯3β,12β,25三醇6-O-β-D-葡萄吡喃糖甙(Ⅰ),其皂甙元亦为一种新皂甙元,其结构为达玛20(22)-烯-3β,12β,6 C,25四醇。三七皂甙B₂经鉴定为已知皂甙人参皂甙(ginsenoside—Rh₁,Ⅱ)。     

多沙唑嗪对映体对兔四种血管α受体的作用

多沙唑嗪(doxazosin，DOX)作为高选择性α₁受体阻断药，是临床上治疗良性前列腺增生(benign prostatic hyperplasia, BPH)的一线药物，但同时引起心血管系统的不良反应。本研究采用兔离体动脉环张力实验及电场刺激兔离体隐动脉诱发交感嘌呤能血管收缩实验观察R-多沙唑嗪(R-doxazosin，R-DOX)和S-多沙唑嗪(S-doxazosin，S-DOX)对兔耳动脉、肠系膜动脉和肺动脉血管平滑肌α₁受体的作用，以及较高浓度R-DOX和S-DOX对兔隐动脉交感神经突触前膜α₂受体的作用。结果表明，在兔耳动脉、肠系膜动脉和肺动脉，R-DOX和S-DOX竞争性拮抗去甲肾上腺素(noradrenaline，NA)诱发的血管收缩反应；其pA₂值分别为7.91±0.03和7.53±0.05，7.80±0.05和7.29±0.07以及8.32±0.06和7.97±0.07；且S-DOX的pA₂值均明显小于R-DOX的pA₂值(P<0.01)。R-DOX和S-DOX(0.1～10 μmol·L^-1)对电刺激诱发的血管收缩反应无明显影响；R-DOX或S-DOX(100 μmol·L^-1)显著抑制电刺激诱发的血管收缩反应，完全抑制外源性NA诱发的血管收缩反应，但对1 mmol·L^-1腺苷三磷酸诱发的血管收缩反应无明显影响。上述结果提示，R-DOX和S-DOX对NA诱发兔耳动脉、肠系膜动脉和肺动脉收缩反应具有竞争性拮抗作用，对上述三种血管S-DOX拮抗NA的pA₂值均明显小于R-DOX。此外，R-DOX和S-DOX的浓度升至10 μmol·L^-1时，对血管交感神经末梢突触前膜α₂受体仍无明显影响。     

人参皂苷Rb1通过JNK/p38 MAPK途径减轻Aβ25-35诱导的胎鼠皮层神经元tau蛋白过度磷酸化

探讨在Aβ_25-35(beta-amyloid peptide (25-35)，Aβ_25-35)诱导的拟阿尔茨海默病样胎鼠皮层神经元tau蛋白过度磷酸化中，人参皂苷Rb1对tau蛋白磷酸化及JNK/p38 MAPK的可能作用。应用蛋白免疫印迹和免疫细胞化学染色的方法，观察tau蛋白磷酸化和JNK(c-jun N-terminal kinase)/p38 MAPK的表达情况。凝聚态Aβ_25-35(20 μmol·L^-1)作用于皮层神经元12 h，tau蛋白的磷酸化水平明显增高，同时JNK/p38 MAPK的总量及其活性形式——磷酸化JNK/p38 MAPK的蛋白表达水平也增加，人参皂苷Rb1可以减轻tau蛋白的磷酸化水平及JNK/p38 MAPK的蛋白水平。人参皂苷Rb1可通过JNK/p38 MAPK途径减轻Aβ_25-35诱导的tau蛋白过度磷酸化。     

慢性孵育β-淀粉样肽(25-35)对培养大鼠海马神经元外向钾电流的影响

目的　研究慢性孵育β-淀粉样肽_(25-35) (β-AP_25-35)对海马神经元上瞬时外向钾电流(I_A)和延迟整流钾电流(I_K)的影响。方法　在培养的大鼠海马神经元上用膜片钳全细胞记录钾通道电流。结果　β-AP_25-35 3μmol·L^-1 孵育细胞24h ,I_K 电流幅度增加(44.3±5.4)% ,电流密度由(30.4±6.4)pA·PF^-1 增加至(43.8±4.7)pA·PF^-1 ;β-AP_25-3510μmol·L^-1 孵育12h ,I_K 电流幅度增加(69.8±4.1) % ,电流密度增加至(51.6±7.9)pA·PF^-1,呈浓度依赖性;β-AP_25-35引起的I_K 增加对TEA 5mmol·L^-1 敏感;β-AP_25-35上调I_K 的作用主要发生在β-AP_25-355用药后48h内。β-AP_25-35对I_A无显著性影响。结论　β-AP_25-35选择性地增加海马神经元上I_K,这一作用可能与β-AP的神经毒性有关     

通光散藤茎的C21甾体成分

为了研究通光散藤茎中的C₂₁甾体类成分，采用不同的色谱方法对通光散藤茎乙醇提取物进行分离纯化，并用波谱学的方法鉴定化合物的结构。从氯仿部位共分离得到8个C₂₁甾体类化合物，其结构分别被鉴定为11α-O-tigloyl-17β-tenacigenin B (1)、 17β-tenacigenin B (2)、 tenacigenoside A (3)、 11α-O-2-methylbutyryl-12β-O-acetyl tenacigenin B (4)、 tenacissoside H (5)、 marsdenoside A (6)、 tenacissoside G (7)和tenacissoside I (8)。其中化合物1为新化合物。     

新的核苷类化合物β-L-D4A的化学合成及体外抗HBV作用

目的以D型谷氨酸为原料，通过一系列化学转化，合成了新的核苷类化合物β-L-D4A，并初步探索其体外抗HBV作用。方法合成β-L-D4A，用红外光谱、核磁共振氢谱和质谱确证目标化合物的结构，以2.2.15细胞(HepG2细胞进行HBV基因组转染后所得)培养为基础，Southern印迹法检测不同浓度化合物体外抑制HNV DNA复制作用，并求出50%抑制的药物浓度，即EC₅₀。以四噻唑蓝(MTT)比色分析法检测不同浓度药物的细胞毒性，求出IC₅₀。结果化合物β-L-D4A经红外光谱、核磁共振氢谱和质谱确证；2.2.15细胞培养上清液病毒DNA的Southern印迹、自显影结果显示病毒的抑制呈明显的浓度依赖性，计算出EC₅₀为0.2 μmol·L^-1，胞内DNA的Southern印迹、自显影显示类似的结果；细胞毒性实验显示IC₅₀为200 μmol·L^-1。结论体外实验显示β-L-D4A具有明显的抑制病毒DNA复制作用，且无明显的细胞毒性，TI值为1 000，高于临床用Lamivudine (750)，有望开发为临床抗HBV用药。     

拟人参皂苷F11在大鼠体内的药物代谢研究

目的探讨拟人参皂苷F11在大鼠体内的药物代谢产物及其过程.方法ip拟人参皂苷F₁₁后,应用TLC分析排泄物中的代谢产物,并利用制备薄层分离制备代谢产物,通过波谱解析(MS,¹HNMR,¹³CNMR,¹H-¹HCOSY)确定其结构.结果从粪便中分离鉴定了3种代谢产物,分别为拟人参皂苷R_T5,ocotillol和1个新的代谢产物F-3-1,并确定其结构为6-O-α-L-吡喃鼠李糖基(1-2)-β-D-吡喃葡糖基-(20S,23S,24R)-达玛-20(24)-环氧-3β,6α,12β,23,25-五醇(6-O-α-L-rhamnopyranosyl-(1-2)-β-D-glucopyranosyl-(20S,23S,24R)-dammar-20(24)-epoxy-3-β,6α,12β,23,25-pentanol).但在尿液和胆汁中并未发现任何代谢产物.结论拟人参皂苷F₁₁不被肝脏代谢,但胆汁排泄物可在肠道被代谢为水解和氧化产物.     

细胞色素P450 CYP2C9*3对格列本脲和氯诺昔康中国人体药代动力学的影响

目的研究人体内细胞色素P450 2C9酶突变等位基因CYP2C9*3对格列本脲和氯诺昔康药代动力学的影响。方法采用PCR-RFLP方法对83名无血源关系的受试者进行CYP2C9*3等位基因的筛查，基因型为CYP2C9*1/*3(n=7)和*1/*1(n=11)的受试者分别参加了格列本脲和氯诺昔康的人体药代动力学试验。采用LC/MS/MS法分别测定受试者口服格列本脲(2.5 mg)和氯诺昔康(8 mg)后不同时刻血浆中格列本脲和氯诺昔康的浓度。结果两组受试者口服格列本脲后，CYP2C9*1/*3组AUC_0-∞显著增加，为CYP2C9*1/*1组的1.5倍，CL/F降低了40%；两组受试者口服氯诺昔康后，CYP2C9*1/*3组AUC_0-∞亦显著增加，为CYP2C9*1/*1组的2.2倍，CL/F降低了55%。结论CYP2C9酶的突变等位基因CYP2C9*3对格列本脲和氯诺昔康的药代动力学有显著性影响。     

Steady-state plasma levels of nortriptyline and its hydroxylated metabolites in Japanese patients: impact of CYP2D6 genotype on the hydroxylation of nortriptyline

The authors investigated the impact of the CYP2D6 genotype on steady-state concentrations of nortriptyline (NT) and its metabolites, trans-10-hydroxynortriptyline (EHNT) and cis-10-hydroxynortriptyline in a Japanese population of psychiatric patients. Forty-one patients (20 men and 21 women) were orally administered nortriptyline hydrochloride. The allele frequencies of the CYP2D6*5 and CYP2D6*10 were 4.9% and 34.1%, respectively. Significant differences in NT concentrations corrected for dose and weight were observed between the subjects with no mutated alleles and those with one mutated allele (mean +/- SD for no mutated alleles vs. one mutated allele: 70.3 +/- 25.4 vs. 98.4 +/- 36.6 ng/mL x mg(-1) x kg(-1); t = 2.54, dcf = 33, p < 0.05) and between the subjects with no mutated alleles and two mutated alleles (no mutated alleles vs. two mutated alleles: 70.3 +/- 25.4 vs. 147 +/- 31.1 ng/mL x mg(-1) x kg(-1); t = 5.87, df = 19, p < 0.0001). Also, a significant difference in the NT/EHNT ratio, which is representative of the hydroxylation ratio of NT, was observed between the subjects with no mutated alleles and those with two mutated alleles (no mutated alleles vs. two mutated alleles: 0.82 +/- 0.30 vs. 2.71 +/- 0.84; t = 7.86, df = 19, p < 0.0001). Multiple regression analysis showed that the number of mutated alleles of CYP2D6, which was the only significant factor, accounted for 41% and 48% of the variability in log(NT corrected for dose and weight) and log(NT/EHNT), respectively.     

CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects

To determine the relationship between CYP3A5 polymorphism and cyclosporine pharmacokinetic parameters among healthy volunteers, an oral cyclosporine (CsA) pharmacokinetic study was performed in 16 healthy subjects. Blood CsA concentrations were measured by high-performance liquid chromatography. Concentration-versus-time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the CYP3A5 using the polymerase chain reaction and pyrosequencing. CsA pharmacokinetic parameters were dichotomized and compared using the 1-way ANOVA test according to the CYP3A5*3C genotype. There were 6 homozygous A/A (wild type), 6 homozygous G/G (variant), and 4 heterozygous A/G genotypes for CYP3A5*3 C in these 16 healthy volunteers. All whites were G/G group, and all African Americans except 1 were either A/A or A/G group. The mean AUC (ng x h/mL) of CsA for the 3 genotype groups were 4962 +/- 1074 (A/A), 6677 +/- 1153 (G/G), and 5416 +/- 1817 (A/G), (A/A versus G/G, P = 0.03), and the mean CL/F (mL/min/kg) were 15.6 +/- 3.1 (A/A), 12.0 +/- 2.3 (G/G), and 14.7 +/- 5.9 (A/G), (A/A versus G/G, P = 0.04). None of the other parameters were significantly different among the 3 genotypes. In conclusion, the CYP3A5*3C polymorphism appears to affect AUC and CL/F of oral CsA significantly in healthy subjects, which may partly explain some of the differences of pharmacokinetics in CsA between African Americans and whites.     

Ritonavir decreases the nonrenal clearance of digoxin in healthy volunteers with known MDR1 genotypes

Our objective was to examine the influence of ritonavir on P-glycoprotein (P-gp) activity in humans by characterizing the effect of ritonavir on the pharmacokinetics of the P-gp substrate digoxin in individuals with known MDR1 genotypes. Healthy volunteers received a single dose of digoxin 0.4 mg orally before and after 14 days of ritonavir 200 mg twice daily. After each digoxin dose blood and urine were collected over 72 hours and analyzed for digoxin. Digoxin pharmacokinetic parameter values were determined using noncompartmental methods. MDR1 genotypes at positions 3435 and 2677 in exons 26 and 21, respectively, were determined using PCR-RFLP analysis. Ritonavir increased the digoxin AUC(0-72) from 26.20 +/- 8.67 to 31.96 +/- 11.24 ng x h/mL (P = 0.03) and the AUC(0-8) from 6.25 +/- 1.8 to 8.04 +/- 2.22 ng x h/mL (P = 0.02) in 12 subjects. Digoxin oral clearance decreased from 149 +/- 101 mL/h x kg to 105 +/- 57 mL/h x kg (P = 0.04). Other digoxin pharmacokinetic parameter values, including renal clearance, were unaffected by ritonavir. Overall, 75% (9/12) of subjects had higher concentrations of digoxin after ritonavir administration. The majority of subjects were heterozygous at position 3435 (C/T) (6 subjects) and position 2677 (G/T,A) (7 subjects); although data are limited, the effect of ritonavir on digoxin pharmacokinetics appears to occur across all tested MDR1 genotypes. Concomitant low-dose ritonavir reduced the nonrenal clearance of digoxin, thereby increasing its systemic availability. The most likely mechanism for this interaction is ritonavir-associated inhibition of P-gp. Thus, ritonavir can alter the pharmacokinetics of coadministered medications that are P-gp substrates.     

C3435T mutation in exon 26 of the human MDR1 gene and cyclosporine pharmacokinetics in healthy subjects

To determine the relationship between C3435T mutation in exon 26 of the human multidrug resistant 1 (MDR1) gene and cyclosporine pharmacokinetic parameters among healthy volunteers, the oral cyclosporine pharmacokinetic study was performed for 14 healthy subjects. Blood cyclosporine concentrations were measured by HPLC. Concentration-time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the C3435T polymorphism of MDR1 gene using the PCR and a restriction digest. Each cyclosporine pharmacokinetic parameter was compared using the Mann-Whitney U test according to his or her P-gp genotype. There were seven (7) homozygous C/C, six (6) C/T, and one (1) homozygous T/T genotypes in these 14 healthy volunteers. According to their genotypes, mean t(max) 1.6 +/- 0.3 hours, mean C(max) 1337 +/- 329 ng/mL, mean Cl/F 66.5 +/- 18.3 L/h, and mean AUC 5642 +/- 1577 ng.h/mL in C/C group and mean t(max) 2.0 +/- 0.6 hours, mean C(max) 1540 +/- 721 ng/mL, mean Cl/F 55.2 +/- 18.9 L/h, and mean AUC 6902 +/- 1405 ng.h/mL in C/T+T/T group. Although Cmax and AUC in C/T and T/T group were 15% and 22% larger than those in C/C group, none of these parameter comparisons was statistically significant. There were no statistical differences in cyclosporine pharmacokinetics among different MDR1 genotypes in these 14 healthy subjects.     

Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects

Simvastatin, a cholesterol-lowering agent, is mainly metabolized by CYP3A4/5. The objective of this study was to investigate the effect of CYP3A5*3 genotype on the pharmacokinetics of simvastatin in humans. Twenty-two men with CYP3A5*1/*1 (n = 4), CYP3A5*1/*3 (n = 8), or CYP3A5*3/*3 (n = 10) genotypes were enrolled. Each subject ingested a 20-mg dose of simvastatin, and plasma simvastatin concentrations were measured for 12 hours after dosing. The mean (+/-SD) area under the plasma concentration-time curve for simvastatin in the CYP3A5*1/*1 carriers (4.94 +/- 2.25 ng x h/mL) was significantly lower than CYP3A5*3/*3 carriers (16.35 +/- 6.37 ng x h/mL; P = .013, Bonferroni test). The mean (+/-SD) oral clearance was also significantly different between CYP3A5*1/*1 carriers (4.80 +/- 2.35 L/h) and CYP3A5*3/*3 carriers (1.35 +/- 0.61 L/h; P < .05, Dunn's test). However, other pharmacokinetic parameters including peak plasma concentrations and half-life did not show any difference between genotype groups. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of simvastatin and provides a plausible explanation for interindividual variability of simvastatin disposition.     

Steady-state plasma levels of E- and Z-10-OH-nortriptyline in nortriptyline-treated patients: significance of concurrent medication and the sparteine oxidation phenotype

Steady-state plasma levels of nortriptyline and E- and Z-10-OH-nortriptyline were determined in 55 depressed patients during long-term treatment. Dose-corrected steady-state levels varied by a factor of 20 for nortriptyline, a factor of 7 for E-10-OH-nortriptyline (sum of enantiomers), and a factor of 12 for Z-10-OH-nortriptyline (sum of enantiomers). The E-10-OH-nortriptyline levels were higher than the corresponding nortriptyline levels in about 50% of the patients and the nortriptyline/E-10-OH-nortriptyline ratio ranged from 0.27 to 4.8. In contrast to E-10-OH-nortriptyline, the steady-state levels of Z-10-OH-nortriptyline correlated significantly with the nortriptyline levels (rs = 0.68, n = 55, p less than 0.001) and the nortriptyline/Z-10-OH-nortriptyline ranged from 1.7 to 10. Patients on concurrent treatment with perphenazine or benzodiazepines had higher nortriptyline and nortriptyline/E-10-OH-nortriptyline ratios than patients taking lithium or no other psychotropic drugs. A sparteine test was carried out in 22 patients and the sparteine metabolic ratio correlated significantly with the dose-corrected steady-state levels of nortriptyline (rs = 0.62, p less than 0.01) and E-10-OH-nortriptyline (rs = -0.52, p less than 0.02) and particularly well with the ratio nortriptyline/E-10-OH-nortriptyline (rs = 0.83). The genetic variability in the sparteine/debrisoquine P-450 isozyme appeared to be clearly more important for the interindividual variation in 10-hydroxylation of nortriptyline than the possible interactions with concurrent medication.     

Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects

This study was to evaluate the combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol, a substrate of both CYP2D6 and CYP3A4, in healthy subjects. Nineteen healthy volunteers whose CYP2D6 genotypes were predetermined were enrolled (9 for CYP2D6*1/*1 and 10 for CYP2D6*10/*10). Four subjects (1 for CYP2D6*1/*1 and 3 for CYP2D6*10/*10) did not complete the study because of adverse events. The pharmacokinetics of haloperidol and its pharmacodynamic effects measured for QTc prolongation and neurologic side effects were evaluated after a single dose of 5 mg haloperidol following a pretreatment of placebo or itraconazole at 200 mg/d for 10 days in a randomized crossover manner. Itraconazole pretreatment increased the mean area under the time-concentration curves (AUCs) of haloperidol by 55% compared to placebo pretreatment (21.7 +/- 11.3 vs 33.5 +/- 29.3 ng h/mL). The subjects with CYP2D6*10/*10 genotype showed 81% higher AUC compared to that of subjects with CYP2D6*1/*1 genotype (27.6 +/- 22.2 vs 50.2 +/- 47.1 ng h/mL). In the presence of itraconazole, subjects with CYP2D6*10/*10 showed 3-fold higher AUC of haloperidol compared to that of placebo pretreated subjects with CYP2D6*1/*1 genotype (21.7 +/- 11.3 vs 66.7 +/- 62.1 ng h/mL; P < 0.05). The CYP2D6*10 genotype and itraconazole pretreatment decreased the oral clearance of haloperidol by 24% and 25%, respectively, but without a statistical significance. In the subjects with both CYP2D6*10 genotype and itraconazole pretreatment, however, the oral clearance was significantly decreased to 42% of subjects with wild genotype in the placebo pretreatment (4.7 +/- 3.6 vs 2.0 +/- 1.9 L/h/kg; P < 0.05). Barnes Akathisia Rating Scale (BARS) of subjects with CYP2D6*10/*10 in the presence of itraconazole pretreatment was significantly higher than that of subjects with CYP2D6*1/*1 genotype in the period of placebo pretreatment. Except for this, all other pharmacodynamic estimations did not reach to statistical significance although each CYP2D6*10 genotype and itraconazole pretreatment caused higher value of UKU side effect and BARS scores. The moderate effect of CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol seems to be augmented by the presence of itraconazole pretreatment.     

Pharmacokinetics of telmisartan in healthy Chinese subjects after oral administration of two dosage levels

To study the pharmacolkinetics of telmisartan in healthy Chinese male subjects after oral administration of two dosage levels, 36 healthy subjects were divided into two groups and given a single oral dose of 40 or 80 mg telmisartan (CAS 144701-48-4, MicardisPlus). A sensitive liquid chromatography-tandem mass spectrometry method (LC-MS-MS) was used for the determination of telmisartan in plasma. Both, a non-compartmental and compartmental method were used for analysis of parameters of kinetics. The main pharmacokinetic parameters of the 40 mg and 80 mg regimen group were as follows: t(max) (1.76 +/- 1.75) h, (1.56 +/- 1.09) h, C(max) (163.2 +/- 128.4) ng/mL, (905.7 +/- 583.4) ng/mL, t1/2 (23.6 +/- 10.8) h, (23.0 +/- 6.4) h, AUC(o-t) (1456 +/- 1072) ng x h/mL, (6759 +/- 3754) ng x h/mL, AUC(o-infinity (1611 +/- 1180) ng x h/mL, (7588 +/- 4661) ng x h/mL, respectively. After dose normalization, there was significant difference for main pharmacokinetic parameters C(max) AUC(o-t) and AUC(o-infinity) between two dosage level groups. The plasma concentration-time profile of telmisartan was characterized by a high degree of inter-individual variability and the disposition of telmisartan in healthy Chinese subjects was dose-dependent. The pharmacokinetic parameters C(max) and AUC(o-inifinity) of the 80 mg regimen group increased to about 5-fold compared to that of the 40 mg regimen group, but there was no significant difference for t(max) and t1/2 between the two dose groups.     

Association of the CYP3A4*1B 5'-flanking region polymorphism with cyclosporine pharmacokinetics in healthy subjects

To determine the relationship between CYP3A4*1B polymorphism and cyclosporine pharmacokinetic parameters among healthy volunteers, the oral cyclosporine pharmacokinetic study was performed in 14 healthy subjects. Blood cyclosporine concentrations were measured by a high performance liquid chromatography. Concentration-time data were analyzed by a non-compartmental method using WinNonLin, and the blood samples were genotyped for the CYP3A4*1B 5'-promotor region using the polymerase chain reaction and a restriction digest. Each cyclosporine pharmacokinetic parameter was compared using the one-way ANOVA test according to his or her CYP3A4*1B genotype. There were four (4) homozygous A/A (wild-type), four (4) homozygous G/G (variant) and six (6) heterozygous A/G genotypes for CYP3A4*1B in these 14 healthy volunteers. The mean AUC/D (ng.hr/mL/mg) of CsA were 21.5 +/- 6.0 (A/A), 11.7 +/- 3.2 (G/G) and 19.2 +/- 2.3 (A/G), P = 0.0103 and the mean CL/F (L/hr) were 49.4 +/- 13.9 (A/A), 83.5 +/- 16.0 (G/G), and 52.5 +/- 5.6 (A/G), P = 0.0024. All other parameters were not significantly different among the three genotypes.