Testing for variants in CYP2C19: population frequencies and testing experience in a clinical laboratory

PurposeWe sought to determine the genotype frequencies for cytochrome p450 enzyme 2C19 variant alleles both in the US pan–ethnic population and various US ethnic groups and to establish the frequency of clinically actionable genotypes.MethodsAnalytical results were obtained from 1,396 consecutive samples submitted for cytochrome p450 enzyme 2C19 genotyping tests and stored in a proprietary database. This database was queried and genotypes and predicted phenotypes established. Anonymized samples were obtained from specimens submitted for cystic fibrosis genotyping that contained ethnicity information. Samples from 357, 149, and 346 individuals self–identified as white, African American, and Hispanic, respectively, were analyzed. In addition, 342 anonymized samples submitted for Ashkenazi Jewish panel testing were analyzed.ResultsSignificant ethnic differences were observed in the frequencies of the *17 ultrarapid allele among the various groups studied. In the pan–ethnic population, 3.8% of tested patients were classified as ultrarapid metabolizers, 24% as extensive metabolizers heterozygous for a *17 ultrarapid allele, 27% as intermediate metabolizers, and 3.5% as poor metabolizers. Using stringent criteria, 7.3% of individuals would have clinically actionable genotypes. In addition, we detected two individuals with a haplotype of *2/*17 and a single individual with a haplotype of *4/*17 indicating that the *17 hypermetabolic allele can occur on a *1, *2, or *4 background.Genet Med 2012:14(1):95–100.     

等位基因特异荧光PCR法检测CYP2C19基因型

目的了解人群CYP2C19基因型的分布,评价等位基因特异荧光PCR法检测CYP2C19基因型。方法等位基因特异荧光PCR法和金标准Sanger DNA直接测序法检测356名供者外周血CYP2C19基因型,实验采用同步盲法。结果 CYP2C19*1/*1型、CYP2C19*1/*2型、CYP2C19*2/*3型、CYP2C19*3/*3型、CYP2C19*2/*2型及CYP2C19*1/*3型的频率分布:使用PCR荧光法检测时分别为46.6%(166/356)、33.2%(118/356)、2.0%(7/356)、0.8%(3/356)、10.7%(38/356)及6.7%(24/356);采用DNA测序法时分别为46.3%(165/356)、33.4%(119/356)、2.0%(7/356)、0.8%(3/356)、11.0%(39/356)及6.5%(23/356)。两种方法检测CYP2C19基因型具有一致性(P=0.392),且一致性较好(Kappa=0.987);两种方法基因型检测结果一致率为99.2%。结论为保障医疗安全,临床需开展CYP2C19基因型检测;等位基因特异荧光PCR法检测CYP2C19基因型简便可靠。     

山东人群华法林稳定剂量预测模型的准确性验证

目的比较5种华法林稳定剂量预测模型以及经验给药方式(2.5 mg/day)对山东人群预测的准确性。方法招募正在或曾经服用华法林并已达到稳定剂量的患者,检测重要的华法林药物代谢基因的型别,收集患者的临床信息,采用预测百分比及绝对误差均值法评价各模型预测的准确性。结果在入组的125例患者中,CYP2C9*1/*1、CYP2C9*1/*3和CYP2C9*1/*2基因型分别占92.00%、7.20%和0.80%。VKORC1-1639 AA、AG、GG基因型分别占82.40%、15.20%、2.40%;CYP4F2*1/*1、*1/*3,*3/*3基因型分别占50.40%、39.20%、10.40%。在其他位点型别固定的情况下,CYP2C9*1/*3和CYP2C9*1/*2基因型个体与CYP2C9*1/*1相比华法林剂量明显降低。VKORC1-1639 AG型与AA型相比华法林稳定剂量增加45%~50%(P<0.05)。CYP4F2*1/*3与CYP4F2*1/*1基因型个体相比,华法林稳定剂量增加约5.9%(P=0.02);CYP4F2*3/*3与CYP4F2*1/*1基因型个体相比华法林剂量增加约13.0%(P=0.129)。预测效果较好的模型包括IWPC(59.20%)、Huang(57.60%)、Ohno(52.80%),绝对误差均值分别为0.35(95%CI:0.11~0.49)、0.15(95%CI:0.10~0.32)、0.39(95%CI:0.12~0.51)。结论CYP2C9、VKORC1、CYP4F2等3个基因的多态性对山东人群的华法林稳定剂量存在影响。IWPC模型更适用于山东人群。     

Genetic polymorphisms and phenotypic analysis of drug-metabolizing enzyme CYP2C19 in a Li Chinese population

CYP2C19 is a highly polymorphic gene and CYP2C19 enzyme results in broad inter-individual variability in response to certain clinical drugs, while little is known about the genetic variation of CYP2C19 in Li Chinese population. The aim of this study was to identify different CYP2C19 mutant alleles and determine their frequencies, along with genotype frequencies, in the Li Chinese population. We used DNA sequencing to investigate promoter, exons, introns, and 3’UTR of the CYP2C19 gene in 100 unrelated healthy Li individuals from Hainan Province, China. We also used SIFT and PolyPhen-2 to predict the protein function of the non-synonymous mutation in CYP2C19 coding regions. We identified 22 different CYP2C19 polymorphisms in the Li Chinese population, including three novel variants (-254A > G, 17807T > C and 58025C > T). The allele frequencies of CYP2C19*1A, *1B, *2A and *3A were 50%, 24%, 24.5%, and 1.5%, respectively. The most common genotype combinations were *1A/*1B (48%) and *1A/*2A (49%). Additionally, the mutation Ala161Pro was predicted to be intolerant and possibly damaging by SIFT and PolyPhen-2, respectively. Our results shed new light on CYP2C19 polymorphisms in Li individuals, which may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group.     

Effect of CYP2C9 gene polymorphisms on response to treatment with sulfonylureas in a cohort of Egyptian type 2 diabetes mellitus patients

Oral hypoglycemics are a widely prescribed group of drugs for the management of type 2 diabetes mellitus. Sulfonylureas (SUs) are the cornerstone of type 2 diabetes pharmacotherapy. The enzyme cytochrome P450 2C9 (CYP2C9) is the main enzyme that catalyzes the biotransformation of SUs. It is encoded by the polymorphic gene CYP2C9 with two allelic variants namely CYP2C9*2 and CYP2C9*3 coding for variant allozymes with reportedly decreased metabolic capacity resulting in decreased SUs clearance and consequently prolonged and exacerbated action. The aim of this study was to investigate the influence of genetic polymorphisms of CYP2C9 on the response to glibenclamide, a second-generation sulfonylurea. Hundred type 2 diabetic patients were enrolled in the study. Genotyping was done on the LightCycler 2 by real-time polymerase chain reaction (PCR) hybridization probe assay. The results are the following: 53 patients were carriers of the wild genotype (CYP2C9*1/*1), 20 were heterozygous for the variant CYP2C9*2 allele (CYP2C9*1/*2), 18 were heterozygous for the variant CYP2C9*3 allele (CYP2C9*1/*3), and 9 were double heterozygous for both mutant alleles (CYP2C9*2/*3); of those double mutant genotype patients, two were also homozygous for the mutant CYP2C9*2 allele (CYP2C9*2/*2) and one patient was homozygous for the mutant CYP2C9*3 allele (CYP2C9*3/*3). Although there was no significant difference in drug dosage between the four groups, there was however a significant association of the CYP2C9*2/*3 genotype with better glycemic control. As conclusion, the better glycemic control observed can probably be attributed to slower metabolism of SUs by the carriers of the CYP2C9*2/*3 genotype and consequently longer half-life or exacerbated effect of the SUs administered.     

The ADH3*2 and CYP2E1 c2 alleles increase the risk of alcoholism in Mexican American men

To identify the association between the polymorphisms of genes encoding alcohol metabolizing enzymes and alcoholism, the alcohol dehydrogenase 2 (ADH2), alcohol dehydrogenase 3 (ADH3), aldehyde dehydrogenase 2 (ALDH2), and cytochrome P450 2E1 (CYP2E1) genes were studied in 101 male Mexican American alcoholics. One hundred and four Mexican American nonalcoholic males served as controls. The allele frequency of ADH2*2 (4.3%) and ALDH2*2 (0%), which are considered as protective alleles against alcohol drinking, is very low in Mexican Americans and no association is found between these alleles and alcohol dependence. A strong association was found between ADH3 genotype and alcoholism; the percentage of subjects who carry the ADH3*2 allele was significantly higher in alcoholics (64.4%) than controls (50%). Association was also found between the CYP2E1 RsaI c2 allele and alcohol dependence; the percentage of subjects who carry the RsaI c2 allele was significantly higher in alcoholics (34.7%) than in nonalcoholics (22.1%). The subjects whose alcohol drinking onset age is younger than 25 have much higher CYP2E1 c2 allele frequency than those whose alcohol drinking onset age is older than 25 (22.1% vs 15.7%). Among 101 alcoholics, only 18 subjects carry neither ADH3*2 nor CYP2E1 c2 alleles. For those subjects who have an ADH*1/*1 background, a strong association is found between CYP2E1 RsaI/DraI genotype and alcoholism; the CYP2E1 RsaI c2 and DraI C allele frequencies are much higher in alcoholics than in nonalcoholics (26.4% vs 9.6% for c2 and 27.8% vs 13.5% for C allele). Taken together, ADH3*2 and CYP2E1 c2/C alleles might independently contribute to the development of alcoholism in Mexican American men.     

CYP3A5基因的多态性及其临床意义的研究

目的 了解中国人群中细胞色素P450 3A5基因CYP3A5的多态性及其基因型与临床功能之间的关联。方法 应用变性高效液相色谱技术对180份样本进行基因变异的检测，并经测序验证；以免疫荧光偏振技术监测12例造血干细胞移植患者环孢素（cyclospofin A，CsA）血浓度，数据经统计学软件分析和处理。结果 180份样本中，共检测出1种等位基因即CYP3A5＊3，其频率为76．1％（274／360）；3种基因型，即纯合子CYP3A5＊1／＊1 10份，占总数的5．6％；杂合子CYP3A5＊1／＊3 66份，占总数的36．7％；纯合子CYP3A5＊3／＊3 104份，占总数的57．8％。12例造血干细胞移植患者中检测出两种基因型，即CYP3A5＊1／＊1 2例和CYP3A5＊l／＊3 10例。CYP3A5＊1／＊ l患者外周血均一化后的CsA浓度与CYP3A5＊1／＊3相比较，前者谷浓度C0较后者低，相差2．3～6．6倍，差异有统计学意义（P〈0．01）；服药后2 h峰值C2亦较后者低，相差1．4～3．8倍，同样差异有统计学意义（P〈0．01）。结论 CYP3A5＊3是中国人群中最主要的多态性，CYP3A5基因型与造血干细胞移植患者血中CsA浓度紧密关联，CYP3A5＊1／＊1比CYP3A5＊1／＊3需要更大剂量的CsA以维持相同的血浓度。应用变性高效液相色谱对CYP3A5进行基因型分型，可以预测患者CYP3A5的功能，进而预测其CsA的需求量，使临床应用CsA更加安全有效和个体化。     

Association between cytochrome P4502D6 (CYP2D6) genotype, antipsychotic exposure, and abnormal involuntary movement scale (AIMS) score

Antipsychotic metabolism cosegregates with the polymorphic cytochrome P4502D6 (CYP2D6) hepatic enzyme. Approximately 5-10% of Caucasians show impaired metabolism associated with nonfunctional alleles. Genotyping determines the number of functional alleles, which is phenotypically not possible. The aim of this study was to investigate associations between CYP2D6 genotype, antipsychotic exposure, and abnormal involuntary movement scale (AIMS) score. Schizophrenic patients (DSM-IV) were genotyped for CYP2D6*1, *3, and *4 alleles by nested polymerase chain reaction. A complete history, including psychiatric symptoms, medications and AIMS score was obtained. Antipsychotic exposure was recorded in dose years [(chlorpromazine equivalents x years)/100]. A linear regression model used AIMS scores as the dependent variable. Genotype, gender, antipsychotic exposure, and interactions were independent variables. The results of the 31 patients studied showed: 20 were homozygous for the *1 allele (*1/*1) and 11 were heterozygous for the *1 allele (i.e. *1/*3 or *4). Age, sex, age of onset, treatment duration, antipsychotic exposure, and AIMS scores did not differ between groups. The interaction between dose years and genotype was significant (P < 0.0055), demonstrating that for (*1/*1) patients, the magnitude of antipsychotic exposure had a greater effect on AIMS score (slope = 0.044) compared with (*1/*3 or *4) patients (slope = 0.001). These results suggest patients with a *3 or *4 allele may have a higher risk for developing antipsychotic induced abnormal movements.     

Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population.

Alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) and cytochrome P-4502E1 (CYP2E1), and then to acetate by aldehyde dehydrogenase (ALDH). Polymorphisms of these ethanol-metabolizing enzymes may be associated with inter-individual difference in alcohol metabolism and susceptibility to alcoholic liver disease. We determined genotype and allele frequencies of ALDH2, CYP2E1, ADH2, and ADH3 in male Korean patients with alcoholic cirrhosis (n=56), alcoholics without evidence of liver disease (n=52), and nondrinkers (n=64) by using PCR or PCR-directed mutagenesis followed by restriction enzyme digestion. The prevalences of heterozygous ALDH2*1/*2 plus homozygous ALDH2*2/*2 in patients with alcoholic cirrhosis (7.1%) and alcoholics without evidence of liver disease (3.8%) were significantly lower than that in nondrinkers (45.3%). The c2 allele frequencies of the CYP2E1 in alcoholic cirrhosis, alcoholics without evidence of liver disease, and nondrinkers were 0.21, 0.20, and 0.20, respectively. Allele frequencies of ADH2*2 in the three groups were 0.78, 0.74, and 0.77 and those of ADH3*1 were 0.94, 0.98, and 0.95. Therefore, we confirmed the observation that the ALDH2*2 gene protects against the development of alcoholism. However, the development of cirrhosis in Korean alcoholic patients was not associated with polymorphisms of ethanol-metabolizing enzymes.     

湖北地区房颤患者VKORC1、CYP2C9基因多态性及其对华法林用量的影响

目的:检测房颤患者维生素K环氧化物还原酶复合物1基因(VKORC1)和细胞色素P450酶2C9基因(CYP2C9)多态性及其对临床使用华法林用量的影响。方法:选择口服华法林抗凝治疗的房颤患者94例,采用PCR扩增和DNA直接测序技术检测患者VKORC1和CYP2C9基因型,同时记录不同基因型患者华法林日用量,比较不同基因型房颤患者华法林日用量的统计学差异。结果:94例房颤患者检出VKORC1 AA型84例,VKORC1AG型10例,CYP2C9*1/*1型88例,CYP2C9*1/*3型6例。不同VKORC1、CYP2C9基因型房颤患者华法林用量不同,VKORC1AA型并CYP2C9*1/*1型和VKORC1AG型并CYP2C9*1/*1型患者华法林日用量均高于VKORC1AA型并CYP2C9*1/*3型患者,VKORC1AA型并CYP2C9*1/*1型患者华法林用量又高于VKORC1AG型并CYP2C9*1/*1型患者。结论:湖北地区房颤患者基因型主要为VKORC1AA型与CYP2C9*1/*1型,少量VKORC1AG型与CYP2C9*1/*3型。VKORC1、CYP2C9基因型是华法林用量的重要影响因素。     

细胞色素P4502D6酶基因多态性与右美沙芬氧化代谢的相？…

目的 探讨中国人右美沙芬氧化代谢多态性的遗传机理。方法 采用聚合酶链反应和限制性片段长度多态性技术,对１１９名健康汉族人的肝细胞色素Ｐ４５０２Ｄ６（ＣＹＰ２Ｄ６）基因型进行分析。结果 ＣＹＰ２Ｄ６＾＊１０Ｂ的基因频率为５８．４％,其中１３名（１０．９％）为野生型（ｗ／ｗ）,３３名（２７．７％）为突变型（ｍ／ｍ）,其余７３名（６１．３％）为杂合子（ｍ／ｗ）。右美沙芬中速代谢者（ｉｎｔｅｒｍｅｄｉａｔ     

Novel mutations in the cytochrome P450 2C19 gene: a pitfall of the PCR-RFLP method for identifying a common mutation

CYP2C19 is a clinically important enzyme involved in the metabolism of therapeutic drugs such as (S)-mephenytoin, omeprazole, proguanil, and diazepam. Individuals can be characterized as either extensive metabolizers (EM) or poor metabolizers (PM) on the basis of CYP2C19 enzyme activity. The PM phenotype occurs in 2–5% of Caucasian populations, but at higher frequencies (18–23%) in Asians. CYP2C19*2 and CYP2C19*3, which are single-nucleotide polymorphisms of CYP2C19, are the main cause of PM phenotyping in homozygotes or compound heterozygotes. We report two novel mutations in the CYP2C19 gene identified by direct sequencing and subcloning procedures. One of these mutations was considered to be CYP2C19*3 by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). This result suggests that mutations classed as CYP2C19*3 might include other mutations. Further studies are needed to clarify the relationship between these novel mutations and enzyme activity.The DDBJ accession number of the novel mutation is AB113829     

Adverse drug reaction monitoring in Jena: Relevance of polymorphic drug metabolizing enzymes for inducing adverse drug reactions

Inter-subject variability in therapeutic drug response and drug toxicity is a major problem in clinical practice. In this field genetic polymorphisms of drug metabolizing enzymes play an important role. In a multicenter study supported by the German Federal Institute for Drugs and Medical Devices (BfArM, Z 12.01-68502-201) adverse drug reactions (ADRs) leading to hospital admission to departments of internal medicine have been registered and evaluated. The aim of the presented part of the study was to look for evident differences in genotypes for polymorphic drug metabolizing enzymes between adverse drug reaction cases and controls. All cases found in the local area – Jena and Weimar – were genotyped for N-acetyl-transferase 2 (NAT2), cytochrom P450 (CYP) 2D6 and 2C19 in comparison to a control population of the same region. The investigation on genotype was carried out for about 2 years (2000–2002). 254 blood samples from patients of the ADR study were analyzed. The genotype of drug metabolizing enzymes was determined by means of polymerase chain reaction using allel specific primers or restriction enzyme analysis. Within all ADRs cases genotyped, no exceptional frequencies for slow acetylators or poor metabolizers (PM) of CYP2D6 or CYP2C19 were found. About 65% of the individuals with ADR genotypically displayed a slow acetylator state. 6.3% PM for CYP2D6, including CYP2D6*3, *4 and *6 alleles, and 2.0% PM frequency for CYP2C19 (*2) have been found in ADR cases. A direct connection between PM genotype and the ADR observed may be assumed only in few of them. Further investigations on genotype and ADR-associated drugs require a much larger sample of patients to obtain more data allowing to focus an association on specific drugs, ADR and polymorphisms genotype of drug metabolizing enzymes might be useful.     

The effect of CYP2C9, VKORC1 genotypes and old age on warfarin pharmacologic sensitivity in korean patients with thromboembolic disease

The therapeutic dose of warfarin is dependent upon intrinsic patient characteristics that are highly variable. We assessed the effects of CYP2C9, VKORC1 1173 C/T polymorphisms, and old age on warfarin dosing and sensitivity by measuring plasma S-/R-warfarin levels in Korean patients. INR and the plasma S-/R-warfarin concentrations were determined in 58 patients who had the VKORC1 1173C/T CYP2C9 genotypes, were on a long-term anticoagulation regimen with warfarin, and took a daily dose of warfarin. The pharmacokinetic sensitivity of warfarin was significantly higher in the CYP2C9 *1/*3 genotypes than in the CYP2C9 *1/*1 genotypes [ratio of S-warfarin concentration/dose, 0.53 vs. 0.21; p=0.01]. Pharmacodynamic sensitivity in older patients (≥ 75 years) with the CYP2C9 *1/*1 and VKORC1 1173 TT genotypes was significantly higher as compared to younger patients (<75 years) [Ratio of INR/S-warfarin concentration, 4.88 vs. 3.41; p = 0.026]. The CYP2C9*3 allele and old age (≥ 75 years) with the VKORC1 1173 T allele were also associated with increased risk of over-anticoagulation. The increase of over-anticoagulation risk and warfarin sensitivity is related to the CYP2C9*3 allele and old age with the VKORC1 1173 T allele in Korean patients with thromboembolic disease. These findings suggest that a lower initial and maintenance dose should be considered for the patients with CYP2C9 *3 allele and advanced age in this patient population. However, due to the limited number of patients in the study population, our finding needs to be confirmed by a larger, well-controlled study.     

Reduced CYP2D6 activity is a negative risk factor for methamphetamine dependence

Because methamphetamine (METH) is metabolized by CYP2D6 at the first step of hydroxylation and demethylation, it is possible that functional variants of CYP2D6 alter susceptibility to methamphetamine-induced dependence. We genotyped CYP2D6*1, *4, *5, *10, and *14 for 202 patients with METH dependence and 337 controls in a Japanese population and found a significant association of the CYP2D6 gene with METH dependence (p=0.0299). The patients had fewer *10 and *14 alleles, which are hypofunction alleles, than the controls. CYP2D6 genotypes were divided into three phenotypes: extensive metabolizers, intermediate metabolizers, and poor metabolizers. There was no poor metabolizer among our Japanese subjects, and intermediate metabolizers of CYP2D6 were significantly fewer in methamphetamine-dependent subjects than in controls (p=0.0212), with an odds ratio of 0.62 (95% confidence interval: 0.51-0.76). The present study demonstrated that reduced CYP2D6 activity was a negative risk factor for methamphetamine dependence.     

中国苗族、布依族、土族和独龙族群体中细胞色素P450 2C19基因座遗传多态性分析

目的 研究细胞色素P450 2C19（cytochrome P450 2C19,CYP2C19）在中国4个民族群体中的基因型和基因频率。方法 采用聚合酶链反应与限制性片段长度多态性技术，分析了无血缘关系的苗族、布依族、土 和独龙族人群的基因型。结果 CYP2C19＊2突变基因在苗族、布依族、土圹和独龙族人群中的频率分别为0.292、0.329、0.315和0.349。4个群体经检验均符合Hardy-Weinberg平衡（P＞0.05）。结论 中国苗族、布族、土族和独龙族人群的CYP2C19＊2突变基因频率与欧洲、非洲人群差异较大，而与亚洲人群相近。     

A case of intolerance to warfarin dosing in an intermediate metabolizer of CYP2C9

We report a case of intolerance to warfarin dosing due to impaired drug metabolism in a patient heterozygous for the CYP2C9*3 allele. A 30-year-old woman with an artificial cardiac pacemaker was taking warfarin to prevent thromboembolism. This patient had an extremely elevated international normalized ratio (INR) of prothrombin time (PT) following standard doses of warfarin and experienced difficulties during the induction of anticoagulation. Genotyping for CYP2C9 revealed that this patient was an intermediate metabolizer with genotype CYP2C9*1/*3. This case suggests the clinical usefulness of pharmacogenetic testing for individualized dosage adjustments of warfarin.     

Allele frequencies of single nucleotide polymorphisms (SNPs) in 40 candidate genes for gene-environment studies on cancer: data from population-based Japanese random samples

Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures. The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms (SNPs) of select genes, which may be included in future gene-environment studies on cancer in Japan. SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan. We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes: CYP1A1, CYP1B1, CYP2C9, CYP2C19, CYP2E1, CYP17A1, CYP19A1, AHR, ESR1, ESR2, ERRRG, PGR, EPHX1, EPHX2, HSD17B2, HSD17B3, GSTM2, GSTM3, GSTT2, GSTP1, NAT1, NAT2, COMT, ADH1A, ADH1B, ADH1C, ALDH2, NOS2A, NOS3, IL1A, IL1B, OGG1, NUDT1 [MTH1], DRD2, DRD3, DRD4, SLC6A4, NR3C1 [GCCR], MTHFR, and NQO1. In the present study, the Japanese allele frequencies were verified by using nationwide population samples.     

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C0) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5*1 and *3 [6986A>G] as well as ABCB1 at exons 21 [2677G>T/A] and 26 [3435C>T] in both liver transplant donors and recipients and in kidney transplant recipients. Of the 152 subjects studied, 84.9% showed a CYP3A5*3/*3 genotype. The total frequency of the allelic variant *3 was 93%. For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C0 levels were significantly lower in patients with one copy of the *1 allele compared to those homozygous for the *3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.