Influence of CYP2D6, CYP3A4, CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers

The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P‐glycoprotein (P‐gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro‐aripiprazole, in 148 healthy volunteers from six bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC‐MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC_0?t, C_max and t_1/2 of aripiprazole were higher and clearance of aripiprazole, AUC_0?t of dehydro‐aripiprazole and ratio dehydro‐aripiprazole/aripiprazole were lower. AUC_0?t of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC_0?t of dehydro‐aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p = 0.023) and AUC_0?t (p = 0.039) and C_max of dehydro‐aripiprazole (p = 0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro‐aripiprazole/aripiprazole than *1/*3 (p = 0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC_0?t of aripiprazole (p = 0.001), especially nausea/vomiting, which were more common in women (p = 0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p = 0.034; p = 0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro‐aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro‐aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs.     

抗结核药物性肝损害与CYP2E1和GSTM1基因多态性的相关性研究

目的:分析抗结核药物性肝损害(ADIH)与细胞色素P450酶(CYP)2E1和谷胱甘肽-S-转移酶(GST)M1基因多态性的相关性,并探讨其易感因素。方法:选择我院2011年10月-2015年6月收治的我国南方汉族肺结核住院患者91例,根据治疗过程中是否出现ADIH将其分为ADIH组(34例)和无ADIH组(57例);抽取患者外周静脉血,分别采用聚合酶链式反应(PCR)和多重PCR法检测其CYP2E1和GSTM1基因多态性,采用Logistic回归分析考察ADIH的易感因素。结果:所有患者CYP2E1基因型均为c2/c2型(100%);GSTM1基因型分布符合Hardy-Weinberg平衡(P>0.05)。ADIH组GSTM1(+/-)基因型患者有9例(26.5%),GSTM1(-/-)基因型患者有25例(73.5%),差异有统计学意义(P<0.05);无ADIH组GSTM1(+/-)基因型患者有17例(29.8%),GSTM1(-/-)基因型患者有40例(70.2%),差异有统计学意义(P<0.05);但GSTM1(+/-)和(-/-)基因型在两组患者中的分布差异均无统计学意义(P>0.05)。Logistic回归分析结果显示,患者性别、年龄、体质量指数和GSTM1基因型与ADIH均无相关性(P>0.05)。结论:患者性别、年龄、体质量指数和GSTM1基因型可能与ADIH无关。由于仅检出1种CYP2E1基因型,尚无法判断其多态性与ADIH的相关性。     

健康人应用4种不同剂型茶碱的药代动力学及生物利用度研究

通过荧光偏振免疫法测定１０名健康人血清中茶碱浓度，对口服茶碱控释片、茶碱缓释片、氨茶碱片及静脉注射氨茶碱进行了药代动力学及生物利用度的研究。结果：控释片达峰时间（ｔｐ＝６．００±０．９３ｈ）与缓释片达峰时间（ｔｐ＝６．００±１．１１ｈ）均慢于氨茶碱片（ｔｐ＝１．８３±０．３８ｈ）；清除率（Ｃｌ＝０．４０±０．１１、Ｃｌ＝０．４１±０．０９ｍｌ／ｍｉｎ·ｋｇ）也均小于氨茶碱片（Ｃｌ＝０．６４±０．１２ｍｌ／ｍｉｎ·ｋｇ），控释与缓释片的生物利用度分别为９４．０±１５．７％、９４．８±１７．２％，高于氨茶碱片（Ｆ＝８７．７±１９．５％）。控释片、缓释片与普通片各药代动学参数及绝对生物利用度间差异均有显著性，而控释片与缓释片间无显著性差异，说明茶碱控释片与缓释片具有满意的缓释特性，保证可靠的完全吸收，减小峰谷浓度落差，并可减少给药次数，降低毒副反应的发生率，提高临床治疗效果。     

Interaction between Erythromycin and Nitrazepam in Healthy Volunteers

Abstract: Interaction between erythromycin, a strong inhibitor of CYP3A4, and nitrazepam, a long-acting benzodiazepine, was investigated in a double-blind and randomized cross-over study of two phases. Ten healthy volunteers received erythromycin (500 mgx3) orally or placebo for 6 days. On the fourth day they were given a challenge dose of 5 mg nitrazepam. Plasma samples were collected and psychomotor effects were measured during 42 hr after intake of nitrazepam. There was a statistically significant pharmacokinetic interaction between erythromycin and nitrazepam. Erythromycin increased the area under the nitrazepam concentration-time curve by 25% (P<0.05) and the peak concentration by 30% (P<0.05). The concentration peak time of nitrazepam was shortened by over 50% (P<0.05). The elimination half-lives did not change. Accordingly, as far as the metabolism of nitrazepam is concerned, erythromycin does not cause any major changes in the metabolism of nitrazepam. In psychomotor performance only minor differences were seen. It is concluded that the interaction between erythromycin and nitrazepam is of little clinical significance.     

Sensorimotor Gating is Associated with CHRNA3 Polymorphisms in Schizophrenia and Healthy Volunteers

Attentional gating deficits, commonly measured by prepulse inhibition (PPI) of the acoustic startle response (ASR), have been established as an endophenotype of schizophrenia. Prepulse inhibition is heritable and has been associated with polymorphisms in serotonin and dopamine system genes. Prepulse inhibition can be enhanced by nicotine, and therefore it has been proposed that schizophrenia patients smoke to ameliorate their early attentional deficits. The PPI-enhancing effects of nicotine in rodents are strain dependent, suggesting a genetic contribution to PPI within the nicotinic acetylcholine receptor (nAChR) system. Recent human genetic studies also imply that tobacco dependence is affected by polymorphisms in the α3/α5 subunits of the nAChR (CHRNA3/CHRNA5) gene cluster. We, therefore, investigated the impact of two common CHRNA3 polymorphisms (rs1051730/rs1317286) on PPI, startle reactivity, and habituation of the ASR in two independent samples of 107 healthy British volunteers and 73 schizophrenia patients hailing from Germany. In both samples, PPI was influenced by both CHRNA3 polymorphisms (combined p-value=0.0027), which were strongly linked. Moreover, CHRNA3 genotype was associated with chronicity, treatment, and negative symptoms in the schizophrenia sample. These results suggest that sensorimotor gating is influenced by variations of the CHRNA3 gene, which might also have an impact on the course and severity of schizophrenia.     

Metabolism and Disposition of Tribendimidine and Its Metabolites in Healthy Chinese Volunteers

Background: Tribendimidine is a new anthelmintic agent synthesized by Chinese scientists. It is a broad spectrum agent with high activity against parasites. However, its disposition and metabolism remain unknown.Objective: To investigate the metabolism, disposition, and metabolites of tribendimidine in healthy human volunteers.Methods: Twelve healthy Chinese volunteers were chosen after clinical assessment of health status and laboratory tests. They received single oral doses of tribendimidine 400mg enteric-coated tablets. Blood and urine samples were collected at scheduled timepoints. Samples were qualitatively and quantitatively analyzed by liquid chromatography-mass spectrometric (LC-MS) and high performance liquid chromatography (HPLC) methods, respectively.Results: Tribendimidine was rapidly and completely broken down to p-(1-dimethylamino ethylimino) aniline (dADT) and terephthalaldehyde (TPAL). Furthermore, dADT was partially transformed to acetylated dADT, and TPAL completely transformed to terephalic acid (TPAC). The main pharmacokinetic parameters (± SD) of dADT were as follows: elimination half life (t_1/2) 4.74 ± 1.80 h; elimination rate constant (K_e) 0.16 ± 0.06 h⁻¹; apparent volume of distribution (Vd/F) 12.23 ± 8.69L • kg⁻¹; apparent total clearance of the drug from plasma (CL/F) 1.63 ± 0.58L • h⁻¹ • kg⁻¹; area under the plasma concentration-time curve (AUC) from time 0 to time 24 hours (AUC₂₄) 4.29 ± 1.88 μg • mL⁻¹ • h; AUC from time zero to infinity (AUC_∞) 4.45 ± 1.81 μg • mL⁻¹ • h; maximum plasma drug concentration (C_max) 0.64 ± 0.27 μg • mL⁻¹; and time to C_max (t_max) 4.20 ± 0.71 h. A total of 35.28% dADT and 28.50% TPAC were excreted through the urine within 24 hours after tribendimidine administration.Conclusion: These results reveal the disposition, metabolism, and main metabolites of tribendimidine in healthy Chinese volunteers.     

CYP2C19、P2Y12基因多态性与缺血性脑卒中患者氯吡格雷抵抗的相关性研究

目的：考察CYP2C19、P2Y12受体的基因多态性与氯吡格雷抵抗的相关性研究.方法：96例中国缺血性脑卒中患者持续服用氯吡格雷75 mg,收集全血提取DNA,采用Sequenom MassARRAY iPLEX（R）基因型分析技术进行CYP2C19＊ 2（681G＞A,rs4244285）、CYP2C19＊3（636 G＞A,rs4986893）及P2Y12受体（52G＞T,rs6809699） （744T＞C,rs2046934）4个SNPs的基因型分析.采用二磷酸腺苷（ADP）诱导光比浊法测定血小板聚集功能.采用Chi-square检验或Fisher确切概率法分析相关性.结果：患者分为氯吡格雷抵抗（CR）组与非抵抗组,CYP2C19＊ 2（rs4244285）及P2Y12受体（rs2046934）基因型分布在两组间的差异有统计学意义（P=0.027,P=0.034）.其中,CYP2C19＊2 GA＋ AA基因型为CR发生的风险因素（OR=2.607,95％CI：1.062～6.399）.CYP2C19＊3（rs4986893）及P2Y12受体（rs6809699）基因型分布在两组比较中差异无统计学意义（P＞0.05）.结论：在中国缺血性脑卒中患者中,CYP2C19＊2（rs4244285） GA＋ AA型与氯吡格雷抵抗的发生密切相关,该基因型检测将有助于指导氯吡格雷的临床合理应用.     

Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis

AIMS: Riluzole is used in a fixed dosing schedule of 50 mg twice daily to treat patients with amyotropic lateral sclerosis (ALS), one form of motor neurone disease. The large variability in the pharmacokinetics of riluzole may be a factor contributing to its limited therapeutic benefit. Riluzole is assumed to be mainly metabolized by the cytochrome P450 enzyme 1A2 (CYP1A2). The aim of the study was to investigate the relationship between CYP1A2 activity and riluzole clearance with a view to optimize drug treatment. METHODS: A group of 30 ALS patients participated in the study. In each patient the CYP1A2 activity was determined using caffeine as a metabolic probe. Riluzole clearance was estimated from serum drug concentration measurements followed by Bayesian fitting. RESULTS: Riluzole clearance and the serum paraxanthine : caffeine (P/C) ratio showed a positive correlation (r = 0.693; P = 0.0002). Linear regression analysis identified the P/C ratio (beta: 1.16) and height (beta: 0.027) as independent predictors of riluzole clearance (adjusted r2 = 0.369). CONCLUSIONS: The P/C ratio, used as measure of CYP1A2 activity, significantly correlated with the riluzole clearance, although only 37% of the observed variability could be explained.     

Association between Cardiovascular Drugs and Chronic Kidney Disease in Non‐Institutionalized Elderly Patients

Concern about the renal safety of commonly used cardiovascular drugs with demonstrated clinical benefit appears to be an obstacle to their use in the elderly. The objective was to describe the relationship between cardiovascular drugs and chronic kidney disease (CKD) in elderly individuals in the real‐life setting. This is an ancillary study of the prospective non‐interventional S.AGE (aged individuals) cohort. General physicians were free to prescribe any drug their patients needed. The participants were non‐institutionalized patients aged 65 years and older treated by their primary physician for either chronic pain or atrial fibrillation or type 2 diabetes mellitus. The estimated glomerular filtration rate (eGFR) derived from the CKD‐EPI formula was determined at inclusion and every year during 2 years of follow‐up. This study comprised 2505 patients aged 77.8 ± 6.2 years. At inclusion, the factors associated with CKD (eGFR < 60 ml/min/1.73 m²) in multivariate analysis were age, female gender, hypertension, heart failure, history of atherothrombotic disease and renin angiotensin system blockers, loop diuretics and calcium channel inhibitors. Introduction of each of these three drug classes during the follow‐up period led to only a small decrease in the eGFR: ?3.8 ± 12.7 (p < 0.0006), ?2.2 ± 12.0 (p < 0.003) and ?1.0 ± 13.4 ml/min./1.73 m² (NS), respectively. Only the introduction of loop diuretics was associated with CKD (OR 1.91, 95% CI: 1.25–2.90; p = 0.002). Renal safety of cardiovascular drugs in the elderly appears acceptable and should not be a barrier to their use.     

中国人CYP3A5和CYP2D6基因多态性与他莫昔芬及其活性代谢物血药浓度的相关性

目的：研究中国汉族人群CYP3A5和CYP2D6基因多态性与乳腺癌患者体内他莫昔芬及其活性代谢物4-羟基他莫昔芬血药浓度的相关性。方法：30例乳腺癌患者,应用PCR方法检测其CYP3A5和CYP2D6基因型,应用LC—MS／MS方法测定患者体内他莫昔芬及其活性代谢物4-羟基他莫昔芬的含量,对试验数据进行统计分析。结果：CYP3A5基因型与乳腺癌患者体内他莫昔芬的浓度差异有统计学意义,比较发现＊1／＊1和＊1／＊3组的他莫昔芬的浓度值明显低于＊3／＊3组（P〈0．01）。CYP2D6基因型与其活性代谢物4-羟基他莫昔芬的浓度差异有统计学意义;＊1／＊1和＊1／＊10两组4-羟基他莫昔芬的浓度值都明显高于＊10／＊10组（P〈0．01）,但＊1／＊1组和＊1／＊10组之间4-羟基他莫昔芬的浓度值差异无统计学意义（P〉0．05）。结论：乳腺癌患者的CYP3A5和CYP2D6基因型影响他莫昔芬的体内代谢,相关基因型的测定可以为他莫昔芬个体化合理用药提供依据。     

Effects of UGT1A1, CYP3A5 and ABCB1 Genetic Variants on Pharmacokinetics of Antihistamine Drug Mizolastine in Chinese Healthy Volunteers

Mizolastine is a selective histamine H1 receptor antagonist for chronic urticaria or allergic rhinitis. We investigated whether the variant genotypes of metabolic enzymes UGT1A1, CYP3A5 and transporter ABCB1 influence pharmacokinetic phenotype of substrate mizolastine in Chinese volunteers. Genotyping of single nucleotide polymorphisms in UGT1A1*6 (G211A), CYP3A5*3 (A6986G) and ABCB1 (C3435T) was determined by the pyrosequencing method. After a single oral dose of 10 mg mizolastine, the plasma concentrations were measured using validated high‐performance liquid chromatography in 24 Chinese healthy volunteers. The results showed that the distributions of wild‐type homozygotes and variant allele carriers (the sum of variant heterozygotes and variant homozygotes) were as follows: 17 cases (70.8%) versus seven cases (29.2%) in UGT1A1*6 genotypes, five cases (20.8%) versus 19 cases (79.2%) in CYP3A5*3 genotypes and seven cases (29.2%) versus 17 cases (70.8%) in ABCB1 3435T genotypes, respectively. There were no significant differences in pharmacokinetic parameters of mizolastine between the variant allele UGT1A1*6, CYP3A5*3 and ABCB1 3435T carriers and the wild‐type homozygotes, and the ratios were as follows: C_max was 101.03%, 86.02% and 105.78%; T_max was 162.35%, 98.98% and 144.90%; AUC_0–28 was 113.04%, 77.35% and 112.71%; and t_1/2 was 95.77%, 72.40% and 100.97%, respectively. In conclusion, these results suggested that the UGT1A1, CYP3A5 and ABCB1 genetic polymorphisms might be not contributed to the interindividual variation of mizolastine pharmacokinetic phenotype in the Chinese population.     

Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population

Objective The frequency of functionally important mutations and alleles of genes coding for xenobiotic metabolizing enzymes shows a wide ethnic variation. However, little is known of the frequency distribution of the major allelic variants in the Russian population.Methods Using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) genotyping assays and the real-time PCR with fluorescent probes, the frequencies of functionally important variants of the cytochromes P₄₅₀ (CYP) 2C9, 2C19, 2D6, 1A1 as well as arylamine N-acetyltransferase 2 (NAT2) and P-glycoprotein (MDR1) were determined in a sample of 290 Russian volunteers derived from Voronezh area.Results CYP2C9*2 and *3 alleles were found with allelic frequencies of 10.5% and 6.7%, respectively. The novel intron-2 T>C mutation at exon 2 +73 bp occurred in 24.8% of alleles. CYP2C19*2 and *3 alleles occurred in 11.4% and 0.3%, respectively. Six persons (2.1%) carried two of these CYP2C19 alleles responsible for poor metabolizing activity. Of all subjects, 5.9% were CYP2D6 poor metabolizers, whereas 3.4% were addressed to ultra-rapid metabolizers (CYP2D6*1×2/*1). The CYP1A1*2A allele was found in 4.7%, *2B in 5.0%, *4 in 2.6%, and the 5-mutations –3219C>T, –3229G>A, and the novel –4335G>A in 6.0%, 2.9% and 26.0% of alleles, respectively. Genotyping of eight different single nucleotide polymorphisms in the NAT2 gene provided in 58.0% a genotype associated with slow acetylation. The MDR1 triple variants G2677T and G2677A in exon 21 had an allelic frequency of 41.9% and 3.3%, respectively, and the variant C3435T in exon 26 one of 54.3%. Frequencies of functionally important haplotypes were calculated.Conclusion The overview of allele distribution of important xenobiotic-metabolizing enzymes among a Russian population shows similarity to other Caucasians. The data will be useful for clinical pharmacokinetic investigations and for drug dosage recommendations in the Russian population.     

CYP2C19基因多态性与沙利度胺抗肺癌疗效和不良反应的关系研究

目的探讨在肺癌治疗中CYP2C19基因多态性与沙利的疗效和不良反应的关系。方法通过检测患者的CYP2C19的基因型及沙利度胺稳态血药浓度,将患者分成EM组和PM组,比较2组疗效和不良反应的差异。结果 77例肺癌患者PM 13例(16.9%)。EM组和PM组的有效率分别为39.1%、30.8%,中位生存期分别为9.0月和8.0月,1年生存率分别为62.5%、46.2%,P<0.05。EM组恶心呕吐、腹泻、眩晕的发生率低于PM组,P<0.05。PM的平均血药浓度要高于EM组,P<0.05。结论 CYP2C19基因多态性对沙利度胺抗晚期肺癌生存期无明显影响,EM患者能够降低化疗后恶心呕吐反应发生率,提示PM患者宜从低剂量开始服用沙利度胺。     

Effect of Polymorphisms on the Pharmacokinetics,Pharmacodynamics and Safety of Sertraline in Healthy Volunteers

Sertraline is a selective serotonin reuptake inhibitor widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P‐glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of this study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty‐six healthy volunteers (24 men and 22 women) receiving a 100‐mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP‐binding cassette subfamily B member 1 (ABCB1), solute carrier family 6 member 4 (SLC6A4), 5‐hydroxytryptamine receptor 2A (HTR2A) and 5‐hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Individuals carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half‐life (T_1/2). Moreover, CYP2C19*17 was related to a decreased AUC and T_1/2. No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate‐lowering effect, directly related to maximum concentration (C_max) and the presence of ABCB1 minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and individuals with higher AUC of sertraline, such as CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T individuals.     

Effects of Nimesulide,Acetylsalicylic Acid,Ibuprofen and Nabumetone on Cyclooxygenase‐1‐ and Cyclooxygenase‐2‐Mediated Prostanoid Production in Healthy Volunteers ex vivo

Abstract: The beneficial actions of non‐steroidal anti‐inflammatory drugs (NSAIDs) have been associated with inhibition of cyclooxygenase‐2 (COX‐2), whereas some of their adverse effects are associated mainly with inhibition of COX‐1. Selective COX‐2 inhibitors reduce the risk of gastrointestinal adverse events, but increase the risk of thromboembolic events pointing to importance of optimal COX‐1/COX‐2 inhibition in drug safety. We compared the effects of acetylsalicylic acid, ibuprofen, nabumetone and nimesulide on COX‐1 and COX‐2 pathways in healthy volunteers in an ex vivo set‐up using single oral doses commonly used to treat acute pain. In a randomized, double‐blind four‐phase cross‐over study, 15 healthy volunteers were given orally a single dose of either acetylsalicylic acid 500 mg, ibuprofen 400 mg, nabumetone 1 g or nimesulide 100 mg. Blood samples were drawn before and 1, 3, 6, 24 and 48 hr after the drug for the assessment of COX‐1 and COX‐2 activity. COX‐1 activity was measured as thromboxane₂ production during blood clotting and COX‐2 activity as endotoxin‐induced prostaglandin E₂ synthesis in blood leucocytes. The data show that after a single oral dose these four NSAIDs have different profiles of action on COX‐1 and COX‐2. As expected, acetylsalicylic acid appeared to be COX‐1‐selective and ibuprofen effectively inhibited both COX‐1 and COX‐2. Nabumetone showed only a slight inhibitory effect on COX‐1 and COX‐2. Nimesulide caused almost complete suppression of COX‐2 activity and a partial reduction of COX‐1 activity. This confirms the relative COX‐2 selectivity of nimesulide.     

Polymorphisms of CYP2A6 and its practical consequences

CYP2A6 is an hepatic enzyme predominantly with some expression in specialized extrahepatic cell types. The CYP2A6 enzyme has a somewhat restricted active site, accepting only a few xenobiotics as substrates. Interest in CYP2A6 has risen considerably after nicotine and some tobacco specific nitrosamines were established as high-affinity substrates for this enzyme. Recently, the organization and structures of the CYP2A gene cluster and several polymorphic alleles of the CYP2A6 gene have been characterized. Two alleles with a point mutation and at least three different types of gene deletion, all leading to deficient gene function, have been found. The frequencies of these alleles vary considerably among different ethnic populations, the deletion alleles being most common in Orientals (up to 20%). The frequency of point mutations are low in all populations studied thus far (< 3%). Several case-control studies have addressed the relationship between CYP2A6 status and smoking habits as well as the role of CYP2A6 polymorphism in lung cancer risk. Studies in Japanese suggest that CYP2A6 poor metabolizer genotypes result in altered nicotine kinetics and may lower cigarette smoking elicited lung cancer risk, whereas similar studies in Caucasian populations have not revealed any clear associations between variant CYP2A6 genotypes and smoking behaviour or lung cancer predisposition.     

CYP1A2 in a smoking and a non-smoking population; correlation of urinary and salivary phenotypic ratios

The use of caffeine as a probe for CYP1A2 phenotyping has been extensively investigated over the last 25 years. Numerous metabolic ratios have been employed and various biological fluids analysed for caffeine and its metabolites. These investigations have used non-smoking, smoking and numerous disease populations to investigate the role of CYP1A2 in possible disease aetiology and for induction and inhibition studies in vivo using dietary, environmental and pharmaceutical compounds. This investigation found that the 17X/137X CYP1A2 metabolic ratio in a 5 h saliva sample and 0-5 h urine collection was not normally distributed in both a non-smoking and a smoking population. The urinary and salivary CYP1A2 metabolic ratio was log normally distributed in the non-smoking population but the smoking population showed a bi- (or tri-)modal distribution on log transformation of both the urinary and salivary CYP1A2 metabolic ratios. The CYP1A2 metabolic ratios were significantly higher in the smoking population compared to the non-smoking population when both the urinary and salivary CYP1A2 metabolic ratios were analysed. These results indicate that urinary flow rate was not a factor in the variation in CYP1A2 phenotype in the non-smoking and smoking populations studied here. The increased CYP1A2 activity in the smoking population was probably due to induction of the CYP1A2 gene via the Ah receptor causing an increase in the concentration of CYP1A2 protein.     

Pharmacokinetic Interaction between Faldaprevir and Cyclosporine or Tacrolimus in Healthy Volunteers: A Prospective,Open‐Label,Fixed‐Sequence,Crossover Study

Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single‐centre, open‐label, fixed‐sequence, crossover study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N = 16) or tacrolimus (TAC) 0.5 mg (N = 16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co‐administered with an additional single dose of CsA (50 mg) or TAC (0.5 mg), followed by an additional 6 days of FDV 120 mg once daily. Intensive blood sampling was performed to assess the PK interaction potential. Assessment of relative BA indicated that exposure to CsA co‐administered with FDV was similar to CsA alone. However, the AUC_τ,ss and C_max,ss of FDV were increased by 23% and 41%, respectively, when FDV was co‐administered with CsA. Exposure to TAC was slightly increased (AUC_0‐∞ increased by 27%, no change in C_max) when TAC was co‐administered with FDV. In contrast, exposure to FDV co‐administered with TAC was similar to FDV alone. No unexpected safety findings arose from the trial. The limitations of the study (use of single, low dose of TAC and CsA, and only healthy volunteers in the trial) are discussed.