Influence of ABCB1 gene polymorphisms on the pharmacokinetics of azithromycin among healthy Chinese Han ethnic subjects

The aim of this study was to evaluate the effects of ABCB1 gene polymorphisms on azithromycin pharmacokinetics in Chinese Han ethnic subjects. In total, 20 healthy volunteers with various ABCB1 genotypes (6 with 2677GG/3435CC, 8 with 2677GT/3435CT, 6 with 2677TT/3435TT) were enrolled. Each was given a single oral dose of 500 mg azithromycin. Plasma concentration was measured for up to 96 h by LC/MS/MS. As shown, C_max was significantly lower among individuals with 2677TT/3435TT genotype (468.0 ± 173.4 ng ? h/ml) than those with 2677GG/3435CC (911.2 ± 396.4 ng ? h/ml, p = 0.013). However, the t_max value was higher among subjects with 2677TT/3435TT (2.0 ± 0.5 h) than those with 2677GT/3435CT (1.6 ± 0.3 h) or 2677GG/3435CC (1.4 ± 0.4 h) genotypes (p = 0.068 and p = 0.026, respectively). Furthermore, the AUC _last tended to be higher among subjects with 2677GG/3435CC than those with 2677GT/3435CT or 2677TT/3435TT genotypes (5000.2 ± 1610.0 vs. 4558.0 ± 805.0 vs. 4131.0 ± 995.1 ng/ml). Our results showed for the first time that azithromycin pharmacokinetics may be influenced by particular polymorphisms of the ABCB1 gene. Individualized dosage regimen design incorporating such information may improve the efficacy of the drug while reducing adverse reactions.     

Does maternal MDR1 C1236T polymorphism have an effect on placental arsenic levels?

To detect whether maternal MDR1 C1236T polymorphism has an effect on placental arsenic levels, 112 mother–placenta pairs were examined. Venous blood samples from mothers were collected to investigate the C1236T polymorphism which was detected by standard PCR–RFLP technique. Placentas were collected to measure arsenic levels by GF-AAS. The MDR1 C1236T genotype frequencies of mothers were found as 30.3% homozygote typical (CC), 51.8% heterozygote (CT) and 17.9% homozygote atypical (TT). The mean placental arsenic level was 62.36 ± 30.43 μg/kg. It was observed that the placental arsenic concentrations were higher in mothers with TT genotype than those with CC and CT genotypes, but this was not statistically significant (p = 0.702). This finding was indicated that fetuses of mothers with TT genotype may be more susceptible to arsenic toxicity as compared to those of with CC and CT genotypes. We believe that this difference warrant further studies with larger study subjects.     

MDR1 (ABCB1) gene polymorphism C3435T is associated with P-glycoprotein activity in B-cell chronic lymphocytic leukemia

Functional single nucleotide polymorphism (SNP) C3435T in exon 26 of the MDR1 ( ABCB1 ) gene encoding the xenobiotic transporter P-glycoprotein (P-gp, MDR1, ABCB1) may influence susceptibility to several diseases as well as clinical outcome of treatment with P-gp substrates. Exposure to environmental chemicals is thought to be involved in the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) and P-gp-transported drugs are used in its treatment; however, little is known about the impact of the C3435T MDR1 SNP in B-CLL. In this study, 110 Caucasian B-CLL patients and 201 healthy controls were genotyped for the MDR1 C3435T SNP. Additionally, P-gp activity was assessed in malignant lymphocytes of 22 untreated B-CLL patients. We observed a higher frequency of carriers of at least one 3435T allele (3435CT and 3435TT genotypes) among B-CLL patients as compared to normal individuals (76% vs . 63%, p=0.027). The genotypes 3435CT and 3435TT were associated with B-CLL, (odds ratio=1.8, 95% confidence interval = 1.1-3.0). Moreover, P-gp activity in B-CLL cells depended on MDR1 genotype, with the highest P-gp activity in 3435CC homozygotes, intermediate in 3435CT heterozygotes and the lowest in 3435TT homozygotes (p=0.042). P-gp activity was also significantly lower in carriers of the T-allele (3435CT/TT genotype) as compared to the non-carriers (3435CC genotype), (p=0.029). Taken together, these data indicate that the MDR1 C3435T SNP may carry an increased risk of developing B-CLL, possibly by virtue of decreased protection against P-gp-substrate carcinogens. The differences in P-gp activity in B-CLL tumor cells related to MDR1 genotype may have implications to the response to chemotherapy with P-gp transported anticancer agents.     

Study of ABCB1 polymorphism frequency in breast cancer patients from Poland

BackgroundThe accumulation of mutagenic substances in the human body may result in DNA metabolism disruption followed by carcinogenesis. As a consequence of mutations in the genes coding for transmembrane protein pumps, the intracellular concentration of xenobiotics may significantly increase. This, in turn, may provoke altered risk for cancer development. The gene known to be the most relevant in the transport of numerous compounds is ABCB1 (also known as MDR1). Numerous mutations and polymorphisms that affect the encoded protein's (PgP) function were identified in this gene.The aim of the study was to define the frequency of 2677G > A,T and 3435C > T polymorphisms in a population of Polish breast cancer patients and to estimate their contribution to cancer development.MethodsThe polymorphism frequency analysis (209 patients vs. 202 control subjects) was performed either by allele-specific amplification (2677G > A,T) or by restriction fragment length polymorphism (RFLP) using the SAU3AI restriction enzyme (3435C > T) followed by verification with hybridization probe assays in a Real-Time system and sequencing.ResultsIn the control group the frequency of individual 2677 genotypes was: wild homozygous GG = 34%, heterozygous G/T or G/A = 52.5% and variant homozygous AA or TT = 13.5%, while the genotype frequency in the group of studied patients was 43.5, 44.5 and 12%, respectively. In the control group, the frequency of individual 3435 genotypes was: CC = 25.4%, CT = 50.2%, TT = 24.4%, while the genotype frequency in the group of studied patients was 23, 46 and 31%, respectively.ConclusionsThus, no significant differences in the studied polymorphism frequencies were observed. It is then suggested that the studied polymorphisms, although probably good candidates in other tissue cancer types, might not be good predictive factors in breast cancer risk or development in Caucasians.     

Análisis farmacogenético de la cinética de absorción de ciclosporina en una población española de pacientes trasplantados cardíacos

ObjectiveTo determine how single nucleotide polymorphisms located on genes MDR1, CYP3A4 and CYP3A5 affect the absorption kinetics of cyclosporine in cardiac transplant patients.MethodWe selected a sample of 30 adult patients having previously undergone a primary cardiac transplant and who had received cyclosporine as an immunosuppressant. During the first month after the transplant, we performed a pharmacokinetic study of each patient to determine values in the cyclosporine concentration area under the 12-hour curve, steady-state cyclosporine concentration, maximum cyclosporine concentration, and time to reach that concentration. Single nucleotide polymorphisms were genotyped in all patients: MDR1 3435C > T, CYP3A4-390A > G and CYP3A5 6986A > G.ResultsBeing a carrier of the T-allele for polymorphism MDR1 3435C > T is associated with higher values in the cyclosporine concentration area under the 12-hour curve (p = 0.01) and in steady-state cyclosporine concentration (p = 0.05), compared with those from patients who do not carry that allele.DiscussionOur results show that genotype differences in MDR1 3435C > T can explain part of the variability in cyclosporine absorption among individuals in the population of Spanish cardiac transplant recipients.     

The MDR1 3435 polymorphism in patients with rheumatoid arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is a multifactorial disease, the pathogenesis of which involves immunological, genetic and environmental factors. P-glycoprotein (P-gp) encoded by the MDR1 gene, is an important transporter for many drugs, xenobiotics and cytokines and may be associated with many immunological processes and apoptosis. The activity of P-gp is genetically determined. Naturally occurring MDR1 polymorphisms have been described and correlated with potential clinical effects. Several mutations in the MDR1 gene have been recognized, but only some of them are associated with P-gp expression. The C3435T polymorphism was found to correlate with the activity of P-glycoprotein. The aim of the study was to evaluate the C3435T MDR1 polymorphism in patients with rheumatoid arthritis and to investigate a possible correlation with disease susceptibility, activity and severity. METHODS: The study was carried out in 92 patients with rheumatoid arthritis and 97 healthy subjects as a control group. The C3435T polymorphism was determined using the PCR-RFLP method. RESULTS: The distribution of C3435TT MDR1 genotypes in RA patients did not differ significantly from that in a control group and was as follows: 3435CC in 25 (26.9%) subjects, 3435CT in 50 (53.8%) and 3435TT in 17 (18.3%). The probability of remission of RA symptoms after therapy with methotrexate and glucocorticosteroids however, was 2.89-fold greater in patients with the 3435TT genotype compared to patients with the genotypes 3435CC and 3435CT. The risk of having an active form of rheumatoid arthritis resistant to therapy with disease-modifying antirheumatic drugs in patients with 3435CC and 3435CT genotypes was 2.89 times greater than in homozygous 3435TT subjects. CONCLUSION: We suggest that the C3435T MDR1 polymorphism is not an important genetic risk factor for RA susceptibility, but that this polymorphism may have an influence on the activity of the disease and its response to therapy with disease-modifying antirheumatic drugs.     

Improved Anti‐Emetic Efficacy of 5‐HT3 Receptor Antagonists in Cancer Patients with Genetic Polymorphisms of ABCB1 (MDR1) Drug Transporter

Chemotherapy‐induced nausea and vomiting (CINV) remains a major adverse effect decreasing quality of life in patients with cancer. Genetic variations among patients may be responsible for part of the lack of efficacy of anti‐emetic drugs. The aim of this study was to investigate how the genetic variants of the drug transporter ABCB1 (MDR1) gene affect anti‐emetic treatment with 5‐HT₃ receptor antagonists. Patients (n = 239) receiving moderately or highly emetogenic chemotherapy and ondansetron or granisetron were included in the study. Anti‐emetic responses were recorded daily. The primary end‐point of the assessment was the total control rates of CINV in the acute and delayed phases after chemotherapy. Genotyping was performed by PCR‐RFLP. In the acute phase, patients with ABCB13435TT, 1236TT or 2677TT genotypes had a higher control rate of CINV than other genotype groups: (64.7% in 3435TT versus 45.7% in 3435CC+CT, p = 0.016; 65.1% in 1236TT versus 46.4% in 1236CC+CT, p = 0.027; 66.7% in 2677TT versus 46.5% in other genotypes, p = 0.021). Subjects carrying homozygous variant alleles together (TT‐TT‐TT) showed a significantly higher protection from nausea and vomiting (67.7% in TT‐TT‐TT versus 47.1% in other genotypes, p = 0.032). After the logistic regression analysis with adjustment for other known covariates, the total control rate was significantly higher in the 3435TT genotype group during the acute phase (p = 0.021). No significant change was found between the total control rates among genotypes in the delayed phase. Each of three 3435TT, C1236TT, 2677TT genotypes of ABCB1 and their combination was associated with about 50% higher anti‐emetic response to 5‐HT₃ receptor antagonists in the acute phase of chemotherapy in patients with cancer receiving moderately or highly emetogenic chemotherapy. ABCB1 (MDR1) genotypes may contribute to predict the anti‐emetic efficacy of 5‐HT₃ antagonists.     

Pesticides and their binary combinations as P-glycoprotein inhibitors in NIH 3T3/MDR1 cells

The purpose of the present study was to assess do selected pesticides as well as their binary combinations act as inhibitors of P-glycoprotein (P-gp) activity of NIH 3T3 mouse fibroblasts stably transfected with human MDR1 gene (NIH 3T3/MDR1). As a result of P-gp inhibition, the increase of intracellular accumulation of a model P-gp substrate fluorescent calcein acetoxymethyl ester was measured. Pesticide and verapamil individual dose–response data were scaled and expressed as percent of maximum effect. Results showed that out of 14 pure pesticides tested, endosulfan, phosalone and propiconazole were nearly as potent as model inhibitor verapamil (EC₅₀ = 1.5 μM), while diazinon showed a lower potency of inhibiting P-gp transport activity (EC₅₀ = 58.4 μM). Concentrations of pesticides that produced the same inhibiting effect (isoboles) were combined binary. Results calculated using the isobole method revealed that diazinon caused synergistic effect in inhibiting P-gp transport activity in all combinations.     

Is Internet addiction transitory or persistent? Incidence and prospective predictors of remission of Internet addiction among Chinese secondary school students

BackgroundInternet addiction (IA) is prevalent among adolescents but it is potentially revertible. Only three Taiwan adolescent studies reported IA remission and a few related factors. We investigated incidence and predictors of remission among Hong Kong Chinese secondary school students with a 12-month longitudinal study.MethodsIA was defined as Chen Internet Addiction Scale (CIAS) score > 63. Validated measures were used to assess students' psychosocial wellbeing at baseline and follow-up.ResultsOf 1545 students with IA at baseline, 1296 (83.9%) provided matched baseline/12-month follow-up data; their data were analyzed. Incidence of remission (CIAS ≤ 63 at follow-up) was 59.29/100 person-years. Significant predictors included: 1) baseline CIAS score (ORa = .95), 2) baseline health belief model (HBM) constructs [perception of having severe IA (ORa = .34), perceived susceptibility to IA (ORa = 0.82), perceived barrier (ORa = 0.95), cue to action from parents (ORa = 0.82), and self-efficacy for reducing Internet use (ORa = 1.13)], and 3) baseline psychosocial health measures [self-esteem (ORa = 1.03), severe depression (ORa = 0.72) and social anxiety (ORa = 0.96)] and their changes over time [depression (ORa = .95), anxiety (ORa = .94), loneliness (ORa = .93), self-esteem (ORa = 1.07), positive affect (ORa = 1.10) and family support (ORa = 1.03)]. Two-thirds (64.3%) of the remission group presented reduced CIAS score > 1.5 SD, and recorded larger improvements in psychosocial status over time than the non-remission group.ConclusionWithout noticeable interventions, incidence of remission was high and related to improvements in psychosocial health. Most of the HBM constructs, and baseline/changes in psychosocial measures predicted remission. Interventions to increase remission should modify these factors.     

Psychiatric disorders,suicidal ideation,and sexually transmitted infections among post-deployment veterans who utilize digital social media for sexual partner seeking

IntroductionDigital social media platforms represent outlets through which individuals may find partners for sexual encounters. Using a sample of US post-deployment military veterans, the current study evaluated the prevalence of digital sex seeking as well as clinical correlates of psychopathology, suicidal ideation, and sexually transmitted infections (STIs).MethodsUsing data from a baseline telephone interview and follow-up internet-based survey, we examined the prevalence of sexual partnering via digital social media platforms in a national sample of 283 US combat veterans.ResultsAmong veterans, 35.5% of men and 8.5% of women reported having used digital social media to meet someone for sex. Individuals who reported having used digital social media to find sexual partners (DSMSP+) as compared to those who did not (DSMSP-) were more likely to be young, male, and in the Marine Corps. After adjusting for sociodemographic variables, DSMSP+ status was associated with post-traumatic stress disorder (OR = 2.26, p = 0.01), insomnia (OR = 1.99, p = 0.02), depression (OR = 1.95, p = 0.03), hypersexuality (OR = 6.16, p < 0.001), suicidal ideation (OR = 3.24, p = 0.04), and treatment for an STI (OR = 1.98, p = 0.04).ConclusionAmong US post-deployment military veterans, DSMSP+ behaviors were prevalent, particularly among men. The association between DSMSP+ behaviors and PTSD, insomnia, depression, hypersexuality, suicidal ideation, and STIs suggest that veterans who engage in DSMSP+ behaviors should be particularly thoroughly screened and evaluated for these psychiatric concerns and counseled on the benefits of safe sexual practices.     

Beijing genotype of Mycobacterium tuberculosis is significantly associated with linezolid resistance in multidrug-resistant and extensively drug-resistant tuberculosis in China

Linezolid (LNZ) is a promising antimicrobial agent for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). To investigate the efficacy of LNZ among MDR-TB and XDR-TB in China, the LNZ susceptibility of 158 MDR-TB isolates from the national drug resistance survey was determined by the minimum inhibitory concentration method. The 158 MDR-TB isolates were also sequenced in the 23S rRNA, rplC and rplD genes conferring LNZ resistance and were typed using spoligotyping to identify the Beijing genotype of Mycobacterium tuberculosis. Overall, the prevalence of LNZ-resistant isolates was 10.8% (17/158) among MDR-TB isolates circulating in China. Beijing genotype was significantly associated with LNZ resistance in MDR-TB and XDR-TB (odds ratio = 4.66, 95% confidence interval 1.03–21.16; P = 0.033). In addition, a higher frequency of LNZ-resistant isolates was observed among XDR-TB strains (60%) compared with the MDR (5.6%; P < 0.001) and pre-XDR groups (12.2%; P = 0.004). Mutations in 23S rRNA and rplC were responsible for only 29.4% of LNZ-resistant M. tuberculosis among MDR-TB isolates, and a novel non-synonymous substitution His155Asp in rplC was first identified to be contributing to low-level LNZ resistance (2 μg/mL) in M. tuberculosis. The unsatisfactory correlation between mutant genotypes highlights the urgent need to investigate another mechanism for LNZ resistance that has not yet been described.     

The influence of CYP2A6 polymorphisms and cadmium on nicotine metabolism in Thai population

We investigated the influence of genetic, cadmium exposure and smoking status, on cytochrome P450-mediated nicotine metabolism (CYP2A6) in 182 Thai subjects after receiving 2 mg of nicotine gum chewing for 30 min. The urinary excretion of cotinine was normally distributed over a 2 h period (logarithmically transformed). Individuals with urinary cotinine levels in the ranges of 0.01–0.21, and 0.52–94.99 μg/2 h were categorized as poor metabolizes (PMs: 6.5%), and extensive metabolizers (EMs: 93.5%), respectively. The majority of EMs (45%) carried homozygous wild-type genotypes (CYP2A6*1A/*1A, CYP2A6*1A/*1B and CYP2A6*1B/*1B), whereas only 1% of PMs carried these genotypes. Markedly higher frequencies of EMs were also observed in all heterozygous defective genotypes including the null genotype (*4C/*4C; 1 subject).A weak but significant positive correlation was observed between total amounts of urinary cadmium excretion and total cotinine excretion over 2 h. Our study shows generally good agreement between CYP2A6 genotypes and phenotypes. Smokers accumulated about 3–4-fold higher mean total amounts of 2-h urinary cadmium excretion (127.5 ± 218.2 ng/2 h) than that of non-smokers (40.5 ± 78.4 ng/2 h). Among the smokers (n = 16), homologous wild-type genotype *1/*1 was significantly the predominant genotype (6/16) compared with other defective allele including *4C/*4C. In addition, 2 h urinary excretion of cotinine in smokers of all genotypes was significantly higher than non-smokers. The proportion of smokers who smoked more than 5 cigarettes/day was significantly higher in EMs in all CYP2A6 genotypes (n = 14) than in PMs (n = 0).     

The association between reduced folate carrier-1 gene 80G/A polymorphism and methotrexate efficacy or methotrexate related-toxicity in rheumatoid arthritis: A meta-analysis

Methotrexate (MTX), the most commonly used anti-rheumatic drug against RA, enters the cell via the action of the reduced folate carrier 1(RFC1). A major polymorphism of the RFC1 gene, 80G/A, has been reported to influence the activity of RFC1, resulting in variable intracellular MTX-polyglutamate (MTX-PG) levels. However, the association studies addressing the RFC1 80G/A polymorphism and MTX efficacy or toxicity in Rheumatoid arthritis (RA) has yielded conflicting results. In the present meta-analysis, we aimed to evaluate the association between the RFC1 80G/A polymorphism and MTX efficacy or toxicity in RA patients. A total 17 studies met our inclusion criteria. Among them, 12 studies with 2049 subjects reported the association between the RFC1 80G/A and MTX response, and 12 studies involving 2627 subjects were on MTX-related toxicity. Meta-analysis revealed significant association between RFC1 80G/A polymorphism and MTX efficacy (odds ratio (OR) for the A allele =  1.29, 95% confidence interval (CI) 1.05–1.67, P = 0.02; for AA genotype: OR =  1.49, 95%CI 1.17–1.907, P = 0.001). However, no association could be detected in the analysis of MTX-related toxicity. Stratification by ethnic population also indicated an association between this polymorphism and MTX efficacy in Asian group (P = 0.002 for A allele; P = 0.003 for AA genotype), but not in the Caucasian group (P = 0.15 for A allele; P = 0.05 for AA genotype). In both Asian and Caucasian sub-groups, no influence of the RFC1 80G/A polymorphism on MTX toxicity can be detected. In conclusion, the RFC1 G80A polymorphism is associated with responsiveness to MTX therapy, but may not be associated with MTX toxicity in RA patients.     

Association of CD40 − 1C/T polymorphism with cerebral infarction susceptibility and its effect on sCD40L in Chinese population

This study aims to determine whether functional polymorphism of CD40 is associated with the cerebral infarction (CI) susceptibility, and to investigate the effect of CD40 gene polymorphism on CD40 mRNA expression in PBMCs and plasma sCD40L concentration. A case–control study was performed in 402 CI patients and 693 controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The expressions of CD40 mRNA and plasma sCD40L concentration were determined. The distribution of TT genotype and the frequency of T allele in CI patients were significantly higher than those in the controls (P < 0.05). The frequency of T allele was also significantly higher in the male subjects and the elder subjects (P < 0.05) when stratified analysis was carried out. The PBMCs from CI patients showed significantly higher CD40 mRNA expression than controls (P < 0.01), the CD40 mRNA expression from TT genotype was higher than other genotypes (P < 0.05). TT genotype subjects also showed the highest plasma sCD40L concentration in the male CI patients (P < 0.01). CD40 − 1C/T polymorphism may interfere CI susceptibility, and the T allele may be associated with increased risk of CI. The CD40 − 1C/T polymorphism is also a regulator of CD40 expression and plasma sCD40L concentration.     

Alteration of serum sex hormonal profile in male gasoline filling station workers in respect to their polymorphism of glutathione S-transferase M1

Alterations in offspring sex ratio at birth and level of serum testosterone in filling-station workers have been reported. To determine the association of glutathione S-transferase M1 (GSTM1) polymorphism with serum levels of total testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) of male filling-station workers, the present study was carried out on 114 gasoline workers and 100 age- and sex-matched controls with no occupational exposure to gasoline. We have found no significant difference between the workers and controls for levels of sex hormones in the presence of active GSTM1 genotype. Among subjects with the GSTM1 null genotype, there was significant difference between exposed and unexposed subjects for the concentration of testosterone (t = 4.37, df = 97, P < 0.001). To investigate whether one null genotype could be compensated by an active genotype for the other isoenzyme, the mean concentrations of sex hormones was compared between the exposed and control groups with respect to their combinations of the GSTM1 and GSTT1 genotypes. The exposed group having either “null GSTM1/positive GSTT1” (t = 2.76, df = 72, P = 0.007) or “null GSTM1/null GSTT1” (t = 4.91, df = 23, P < 0.001) combinations had a lower testosterone compared with the controls. It seems that GSTM1 polymorphism has more effect on serum testosterone compared to the GSTT1 polymorphism, in exposed workers.     

Significance of the genetic polymorphism of CYP2D6 and NAT2 in patients with inflammatory bowel diseases

BackgroundThe main types of inflammatory bowel diseases (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). There is evidence that, in addition to immunological and environmental factors, genetic factors also play an important role in the pathogenesis of IBD. Determination of polymorphism of CYP2D6 and NAT2 genes encoding I and II phase enzymes of xenobiotic biotransformation may have clinical value as an indicator of individual predisposition to diseases, and also contribute to effective and safe pharmacotherapy. The aim of this study was to investigate the association between genetic polymorphism of CYP2D6 and NAT2 and the incidence of IBD, including UC and CD, among inhabitants of central Poland.MethodsThe study was performed in 258 individuals from central Poland (115 patients with IBD, including 65 patients with UC and 50 with CD; and in 143 healthy controls). The CYP2D6 genotypes of oxidation and NAT2 genotypes of acetylation were analyzed using the PCR-RFLP method.ResultsThere were no statistically significant differences in the frequency of the CYP2D6 genotypes and alleles in patients with IBD, UC and CD in comparison with the control group. The relative risk (OR) of IBD, UC and CD was higher in carriers of the allele NAT2*7 and was OR = 3.49 (p = 0.0019), OR = 3.86 (p = 0.0019), and OR = 3.02 (p = 0.0247), respectively.ConclusionsPolymorphism of the gene encoding CYP2D6 does not affect the incidence of inflammatory bowel diseases. The carriers of the NAT2*7 allele which determines slow acetylation may be more predisposed to inflammatory bowel diseases, including ulcerative colitis and Crohn's disease.     

Comparison of bidirectional lamivudine and zidovudine transport using MDCK,MDCK–MDR1, and Caco-2 cell monolayers

Bidirectional transport studies were conducted using Caco-2, MDCK, and MDCK–MDR1 to determine P-gp influences in lamivudine and zidovudine permeability and evaluate if zidovudine permeability changes with the increase of zidovudine concentration and/or by association of lamivudine. Transport of lamivudine and zidovudine separated and coadministrated across monolayers based on these cells were quantified using LC–MS–MS. Drug efflux by P-gp was inhibited using GG918. Bidirectional transport of lamivudine and zidovudine was performed across MDCK–MDR1 and Caco-2 cells. Statistically significant transport decrease in B → A direction was observed using MDCK–MDR1 for zidovudine and MDCK–MDR1 and Caco-2 for lamivudine. Results show increased transport in B → A and A → B directions as concentration increases but data from P_app increase in both directions for both drugs in Caco-2, decrease in MDCK, and does not change significantly in MDCK–MDR1. Zidovudine transport in A → B direction increases when coadministrated with increasing lamivudine concentration but does not change significantly in B → A direction. Zidovudine and lamivudine are P-gp substrates, but results assume that P-gp does not affect significantly lamivudine and zidovudine. Their transport in monolayers based on Caco-2 cells increase proportionally to concentration (in both directions) and zidovudine transport in Caco-2 cell monolayer does not show significant changes with lamivudine increasing concentrations. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4413–4419, 2009     

Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in bipolar disorder and major depression

Experimental data suggest that the endogenous cannabinoid system is involved in mood regulation, but no study has been performed so far to investigate the role of endocannabinoid genes in the susceptibility to major depression (MD) and/or bipolar disorder (BD). We assessed the CB1 receptor gene (CNR1) single nucleotide polymorphism (SNP) rs1049353 (1359 G/A) and the fatty acid amide hydrolase (FAAH) gene rs324420 SNP (cDNA 385C to A) for their associations with MD and/or BD in 83 Caucasian patients with recurrent MD, 134 Caucasian individuals with BD, and 117 Caucasian healthy subjects. The distribution of the CNR1 1359 G/A genotypes and alleles significantly differed among the groups (χ² = 12.595; df = 4, P = 0.01 for genotypes; χ² = 13.773; df = 2, P = 0.001 for alleles) with MD patients showing a higher frequency of both AG, GG genotypes and A allele as compared to healthy controls. The distribution of the FAAH cDNA 385C to A genotypes, according to the CC dominant model (AA + AC vs. CC), significantly differed among the groups (χ² = 6.626; df = 2, P = 0.04), with both BD patients and MD patients showing a non-significant slightly higher frequency of the AC genotype. These findings, although preliminary, suggest that the CNR1 1359 G/A and the FAAH cDNA 385C to A gene variants may contribute to the susceptibility to mood disorders.