Comparison of SLCO1B1 sequence variability among German, Turkish, and African populations.

Background: OATP1B1 is one of the key hepatocellular uptake transporters providing extraction of diverse compounds, including bile acids, xenobiotics, and a variety of drugs, from portal venous blood into the liver. Polymorphisms of the SLCO1B1 gene have been demonstrated to influence in vitro transport function and the pharmacokinetic profile of compounds.

Objective: The goal of our study was the comparison of SLCO1B1 gene sequence variability in three ethnic groups as a basis for future genetic association studies.

Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn's disease.

Background: The role of the single nucleotide polymorphisms (SNPs) on positions 2677G>T/A and 3435C>T of the multi-drug-resistance gene 1 (MDR1) in inflammatory bowel disease (IBD) remains unclear.

Aims: To further elucidate the potential impact of MDR1 two-locus genotypes on susceptibility to IBD and disease behaviour.

Patients And Methods: Three hundred eighty-eight German IBD patients [244 with Crohn's disease (CD), 144 with ulcerative colitis (UC)] and 1,005 German healthy controls were genotyped for the two MDR1 SNPs on positions 2677G>T/A and 3435C>T.

Association of MDR1 genotypes with susceptibility to colorectal cancer in older non-smokers.

Objective: The multidrug resistance gene 1 (MDR1) seems to play a role in the carcinogenesis of colorectal tumors. The importance of MDR1 SNPs 2677G > T/A in exon 21 and 3435C > T in exon 26 for cancer susceptibility, however, has not yet been clearly defined.

Methods: Two hundred and eighty-five colorectal cancer patients and 275 controls from five hospitals in the European part of Russia were genotyped for the polymorphisms -129T > C (rs3213619) in exon 1b, 2677G > T/A (rs2032582), and 3435C > T (rs1045642) in this population-based case-control study.

Genotype and phenotype relationship in drug metabolism.

Pharmacogenetics, one of the fields of clinical pharmacology, studies how genetic factors influence drug response. If hereditary traits are taken into account appropriately before starting drug treatment, the type of drug and its dosage can be tailored to the individual patient's needs. Today, the relationships between dosage requirements and genetic variations in drug-metabolizing enzymes such as cytochrome P450 (CYP) 2D6, CYP2C9, and CYP2C19 or in drug transporters such as p-glycoprotein (ABCB1) and OATP-C (SLC21A6) are substantiated best.

In-vitro transport characteristics discriminate wild-type ABCB1 (MDR1) from ALA893SER and ALA893THR polymorphisms.

Background: Genetic variation of the human ABCB1 (P-glycoprotein; MDR1 gene product) efflux transporter is strongly suggested as a determinant factor governing the pharmacokinetics of diverse drugs and xenobiotics. Despite various efforts to associate polymorphisms in ABCB1 to actual clinical effect and transport function, information is still inconsistent or even controversial.

Methods And Results: Using membrane vesicle preparation from ABCB1-expressing HighFive insect cells, we report here that saturation kinectic parameters of the frequently occurring ABCB1 triallelic variants 893Ser (exon 21, 2677T) and 893Thr (2677A) were considerably different from wild-type 893Ala (2677G), despite similar protein expression levels.

Influence of the SLCO1B1*1b and *5 haplotypes on pravastatin's cholesterol lowering capabilities and basal sterol serum levels.

We previously showed that variant SLCO1B1 haplotype *1b (A388G) accelerates and that *5 (T521C) delays hepatocellular uptake of the HMG-CoA reductase inhibitor pravastatin [Mwinyi et al. (2004): Clin Pharmacol Ther 75:415-421]. In the present study we checked for differential effects of variant SLCO1B1 haplotypes on hepatocellular cholesterol synthesis.

[Implications of pharmacogenetics in every-day practice].

Pharmacogenetics as one of the areas of clinical pharmacology addresses hereditary factors involved in individually different responses to drugs. Clinical trials combined with molecular genetics seek for underlying reasons influencing efficacy and toxicity of drugs. The declared goal of pharmacogenetics is to provide physicians with knowledge and tools to allow an individualized patient-directed pharmacotherapy.

[Clinical drug investigations. Definition of terms].

Implementation of the European Directive 2001/20/EC led to the inclusion of definitions for clinical trial and non-interventional trial in German Drug Law. Other terms, such as non-commercial clinical trial, single patient use, post marketing surveillance and public health study are less well defined. This article explains the various terms by comparing their differences and similarities.

Quantification of pravastatin in human plasma and urine after solid phase extraction using high performance liquid chromatography with ultraviolet detection.

A high performance liquid chromatography (HPLC) method for the estimation of pravastatin in human plasma and urine samples has been developed. The preparation of the samples was performed by automated solid phase extraction using clonazepam as internal standard. The compounds were separated by isocratic reversed-phase HPLC (C(18)) and detected at 239 nm.

Pharmacogenetics-based new therapeutic concepts.

Pharmacogenetics, one of the fields of clinical pharmacology, studies how genetic factors influence drug response. If hereditary traits are taken into account appropriately before starting drug treatment, the type of drug and its dosage can be tailored to the individual patient's needs. Pharmacogenetics adds a considerable amount of stringency to the doctor's therapeutic approach.

Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics.

Objective: We compared the pharmacogenetic effects of OATP-C (organic anion transporting polypeptide C) *1a, *1b (A388G), and *5 (T521C) haplotypes on single-dose pharmacokinetics of pravastatin in white subjects.

Methods: Thirty healthy white male subjects were grouped according to their OATP-C haplotype. Each group contained 10 individuals who were either homozygous or heterozygous carriers of the *1a, *1b, or *5 haplotype.

Impact of genetic polymorphisms in transmembrane carrier-systems on drug and xenobiotic distribution.

Active transport across biological membranes has become a noticeable factor in the absorption, distribution, and excretion of an increasing number of drugs. Different transmembrane transport systems including organic anion transporters (OATP, solute carrier family SLC21A), organic cation transporters (OCT, SLC22A), dipeptide transporters (PEPT, SLC15A), nucleoside transporters (CNT, SLC28A), monocarboxylate carriers (MCT, SLC2A), and members of the large ATP-binding cassette family (ABC, SLC3A) are involved in drug disposition. Genetic polymorphisms in transport proteins frequently occur and contribute to interindividual differences in the efficacy and safety of pharmatherapy.

Constitutive rat multidrug-resistance protein 2 gene transcription is down-regulated by Y-box protein 1.

Background/aims: Molecular mechanisms underlying transcriptional rat multidrug-resistance protein 2 (Mrp2, Abcc2) gene regulation are mostly unclear. Given the presence of putative binding sites for the Y-box binding protein YB-1 in the regulatory sequence, its trans-regulatory influence was analyzed.

Methods: Reporter assays in HepG2 cells with various Mrp2 deletion constructs in the absence and presence of co-transfected YB-1 were performed.

MDR1 polymorphisms G2677T in exon 21 and C3435T in exon 26 fail to affect rhodamine 123 efflux in peripheral blood lymphocytes.

P-glycoprotein (Pgp) is a member of the ABC-transporter family, and in humans, is encoded by the MDR1 gene. Recently, several single-nucleotide polymorphisms in the MDR1 gene were identified. The aim of the present study was to evaluate the effect of the MDR1 genetic polymorphisms G2677T and C3435T on Pgp activity in CD56+ and CD4+ peripheral blood cells.

Effects of proinflammatory cytokines on rat organic anion transporters during toxic liver injury and cholestasis.

Hepatobiliary transporters are down-regulated in toxic and cholestatic liver injury. Cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) are attributed to mediate this regulation, but their particular contribution in vivo is still unknown. Thus, we studied the molecular mechanisms by which Ntcp, Oatp1, Oatp2, and Mrp2 are regulated by proinflammatory cytokines during liver injury.

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.

Implications of pharmacogenetics for individualizing drug treatment and for study design.

Adverse drug reactions and ineffective drug treatment are responsible for a large health care burden. Considerable variability in drug response makes the prediction of the individual reaction difficult. Pharmacogenetics can help to individualize drug treatment in accordance with the genetic make-up of the patient.

Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat.

Background/aims: Estrogen-mediated cholestasis is an important clinical entity, but its molecular pathophysiology is still not fully understood. Impaired sodium-dependent uptake of bile acids has been associated with diminished expression of a basolateral Na(+)/bile acid cotransporter (Ntcp), whereas sodium-independent uptake is maintained despite a down-regulation of the organic anion transporter Oatp1. Thus, expression of the two other rat Oatps (Oatps2 and -4) was determined in estrogen-induced cholestasis.

MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males.

Aims: A noncoding single nucleotide polymorphism (SNP) in exon 26 3435C > T of the highly polymorphic MDR1 gene has been demonstrated to alter digoxin absorption after induction of the MDR1 gene product P-glycoprotein by rifampicin or after multiple oral dosing. The aim of the study was to investigate the effects of the major known MDR1 SNPs on the absorption of digoxin after a single oral dose in a large sample without drug pretreatment.

Methods: Fifty healthy white male subjects between the age of 18 and 40 years were enrolled.

Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene.

Objective: We investigated the effect of polymorphisms in the P-glycoprotein (P-gp) MDR1 gene on steady-state pharmacokinetics of digoxin in Caucasians. According to earlier data, homozygous TT of the exon 26 complementary deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P-gp expression in the human intestine.

Methods: Eight healthy male homozygous carriers of the wild-type exon-26 3435C>T (CC), 8 heterozygous subjects (CT), and 8 homozygous mutant (TT) subjects were selected.

Functional analysis of the rat bile salt export pump gene promoter.

The 5' flanking region of the bile salt export pump (Bsep) gene was systematically analysed to provide the basis for understanding the mechanisms which regulate Bsep transcription. In addition substrates and drugs were investigated for their ability to alter Bsep promoter activity. Bsep promoter function was restricted to hepatocyte derived HepG2 cells.

Hepatobiliary organic anion transporters are differentially regulated in acute toxic liver injury induced by carbon tetrachloride.

Background/aims: Hepatobiliary transporters are down-regulated in cholestasis, but their expression in acute, non-cholestatic, cytokine-mediated liver injury is unknown. Thus we studied the molecular mechanisms, by which sodium taurocholate cotransporting polypeptide (Ntcp), organic anion transporting polypeptide 1 (Oatp1), Oatp2, Oatp4, multidrug-resistance protein 2 (Mrp2) and bile salt export pump (Bsep) are regulated in liver injury induced by carbon tetrachloride (CCl(4)).

Methods: mRNA and protein levels were determined in rats 24 and 72h after CCl(4) injection.

Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease.

Although three common MTHFR polymorphisms (C677T, A1298C, T1317C) have been reported, only polymorphism C677T has been investigated intensively as a risk factor for coronary artery disease (CAD). We investigated polymorphism frequencies, allelic associations and the effect of the resulting MTHFR genotypes on total plasma homocysteine (tHcy) levels and on coronary risk in a case-control study with 1000 angiographically confirmed Middle-European CAD patients and 1000 matched controls. Three out of four theoretically possible MTHFR haplotypes were detected: *1 (677C, 1298A), *2 (677T, 1298A), and *3 (677C, 1298C).

Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects.

Background: P-glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment. Various polymorphisms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein expression and oral bioavailability of digoxin.