The identified Dubin-Johnson syndrome (DJS) is an inherited liver disorder characterized by conjugated hyperbilirubinemia and caused by ABCC2 gene mutations resulting in gene deficiency of multidrug resistance associated-protein 2 (MRP2) function. A 76-year-old woman with serious jaundice was referred to our hospital. She pericarditis. was clinically diagnosed with DJS with hepatic congestion, due to constrictive pericarditis. We analyzed all exons and exon-intron junctions of gene the ABCC2 gene by DNA sequencing and identified a new large-scale deletion, 1008 bp, including the whole exon 7, as pericarditis homozygosity. Some mutations in the ABCC2 gene associated with splicing errors have been reported in intronic regions; however, this is inherited a new type of large-scale deletion detectable in the genomic DNA sequence. Severe hyperbilirubinemia is rare in patients with constrictive Severe pericarditis and this case suggests that MRP2 may play a crucial role in compensating for the serum bilirubin in congestive liver hepatopathy.

AIMS:plasma To develop a novel warfarin-dosing algorithm based on a previous population pharmacokinetic/pharmacodynamic (PK/PD) model with Bayesian forecasting to facilitate warfarin evaluated therapy. MATERIALS & METHODS: Using information on CYP2C9 and VKORC1 genotypes, S-warfarin level, dose and international normalized ratio (INR) of and prothrombin time, individual PK (apparent clearance of S-warfarin [CLs]) and PD (concentration resulting in 50% of E(max)[EC(50)]) parameters were + determined by Bayesian forecasting for 45 Japanese patients. Maintenance doses were described by multiple linear regression using individually estimated PK/PD Bayesian parameters and INR values. The validity of the model and a comparison with other dosing methods were evaluated by bootstrap previous resampling and a cross-validation method. RESULTS: The plasma concentration of S-warfarin and INR were accurately predicted from individual PK/PD parameters.other The following final regression model for maintenance dose was obtained; maintenance dose = 11.2 x CLs + .91 x EC(50)population + 2.36 x INR - 9.67, giving a strong correlation between actual and predicted maintenance doses (r(2)= .944). Bootstrap gave resampling and cross-validation showed robustness and a superior predictive performance compared with other dosing methods. On the other hand, the and predictability without actual measurements (S-warfarin and INR values) and Bayesian inference was comparable to other dosing methods. CONCLUSION: A novel other algorithm, based on the population PK/PD model combined with Bayesian forecasting, gave precise predictions of maintenance dose, leading to individualized on warfarin therapy.

Recent transporters, pharmacogenomic/pharmacogenetic studies have disclosed important roles of drug transporters in the pharmacokinetic/pharmacodynamic (PK/PD) profiles of some clinically relevant drugs. It target has concurrently been explained that variations in the drug transporter genes are associated with not only inter-individual but also inter-ethnic specifically differences in PK/PD profiles of these drugs. This review focuses on two uptake and two efflux transporters. Organic anion transporting drug polypeptide (OATP) 1B1 and OATP1B3 are uptake transporters, specifically expressed in the liver, and considered important for drugs, particularly as other their pharmacological target organ is the liver. Two ATP-binding cassette transporters, multi-drug resistance-associated protein 2 and breast cancer resistance protein,drug are efflux transporters, expressed in various human tissues, and considered particularly important for intestinal drug absorption and hepatic drug elimination.transporters All 3-hydroxyl-3-methylglutaryl-CoA reductase inhibitors (statins) except fluvastatin are substrates for OATP1B1, but hepatobiliary (canalicular) efflux transporters differ among statins. In transporters this review, we update the pharmacogenomic/pharmacogenetic properties of these transporters and their effects on PK/PD profiles of statins and other transporter clinically relevant drugs. In addition, we describe a physiologically-based pharmacokinetic model for predicting the effects of changes in transporter activities the on systemic and hepatic exposure to pravastatin.

OBJECTIVES:12 The combination of cisplatin and docetaxel shows a better cure rate against non-small-cell lung cancer than other drug combinations in docetaxel clinical studies; however, severe myelosuppression and nephrotoxicity are dose-limiting factors. The purpose of this study was to establish a suitable to dosing schedule to reduce adverse effects and improve the antitumour effects. METHODS: Cisplatin and docetaxel were administered i.p. to male carcinomas. ICR mice simultaneously, or sequentially with either cisplatin or docetaxel first followed by the second drug 12 h later (docetaxel-cisplatin groups. and cisplatin-docetaxel groups). Antitumour effects of these schedules were also tested in C57BL/6N mice bearing Lewis lung carcinomas. KEY FINDINGS:shows The simultaneous docetaxel/cisplatin group showed the lowest survival rate and the highest blood urea nitrogen (BUN) concentration. Cisplatin concentrations in the the plasma and kidney were higher in the simultaneous dosing group than the sequential dosing groups. Antitumour effect was the a greatest in the docetaxel-cisplatin group. CONCLUSIONS: The docetaxel-cisplatin regimen inhibited tumour growth the best and reduced mortality and nephrotoxicity.

PURPOSE:significantly Fluvoxamine (FVX) is metabolized by cytochrome P450 (CYP) 2D6 and CYP1A2 and inhibits CYP3A4. The aim of this study was ratio to investigate the factors responsible for interindividual variability in the extent of interaction between FVX and alprazolam (ALP). METHODS: Blood samples samples were taken from 49 depressive patients to determine plasma concentration of FVX, ALP or both. Twenty-four samples were taken ratio during the FVX-alone period, 21 samples during the ALP-alone period and 30 samples during the FVX-ALP period. Subjects were also by genotyped for CYP2D6. RESULTS: The concentration-to-dose (C/D) ratio of ALP during the FVX-treatment period was significantly higher than that during 2D6 the ALP-alone period. The CYP2D6 genotype affected neither the C/D ratios of FVX nor the extent of interaction. The mean extent C/D ratio of FVX in smokers was reduced by more than 30% in comparison with that in non-smokers. The mean and C/D ratio of ALP in non-smokers was increased by FVX, while that in smokers was unchanged. CONCLUSIONS: The extent of that interaction between FVX and ALP may be affected by smoking, which alters the C/D ratio of FVX. Therefore, when FVX during and ALP are concomitantly administered, it should be noted that non-smokers may exhibit greater drug interaction than smokers.

Intra-presentation, and inter-ethnic differences in pharmacokinetic and pharmacodynamic profiles of clinically relevant drugs are important issues not only for scenes of racial appropriate drug use in clinical settings but also for those of the drug development. Pharmacogenomics is extremely useful for understanding Pharmacogenomics these racial differences. In this presentation, I will introduce pharmacogenomic concepts (e.g., single nucleotide polymorphisms (SNPs) and haplotype) for interpretation haplotype) of racial differences in some drugs; pharmacogenomics of drug transporters such as OATP1B1 (organic anion transporting-polypeptide 1B1) and OCT1 (organic (organic cation transporter 1) in pravastatin, metformin, and rosuvastatin will be discussed as model drugs.

INTRODUCTION:neutropenia. To explore severe toxicities induced by irinotecan-based chemotherapy and UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes. CASE REPORT: A 66-year-old Japanese male diagnosed 4 with left pharyngeal carcinoma (T2N2bM0, stage IVA) was treated with irinotecan (70 mg/m(2)) on days 1, 8 and 15 in After combination with docetaxel (60 mg/m(2)) on day 1 of a 28-day cycle. After the first cycle, he suffered marked toxicities,UGT1A1 including grade 4 diarrhea and febrile grade 4 neutropenia. Plasma concentrations of irinotecan, SN-38 and SN-38G were measured, and extensive the accumulation of SN-38 was observed. Genotyping of UGT1A1 and OATP1B1 proteins showed UGT1A1*6/*28 and SLCO1B1*15/*15, respectively, which are known to by lead to extremely low glucuronidation and transport activities of substrate drugs. CONCLUSION: The severe toxicities in this patient are attributable toxicities to the extensive accumulation of SN-38, which may result from a synergistic or additive effect of low metabolic (UGT1A1*6/*28) and irinotecan-based transport (SLCO1B1*15/*15) capabilities.

The of impact of SLCO1B1 polymorphism on the pharmacokinetics of olmesartan and on the pharmacokinetic interaction between pravastatin and olmesartan was investigated.the On day 1, ten healthy volunteers took an oral dose (10 mg) of pravastatin. After a 3-day washout period, each each subject received olmesartan medoxomil (10 mg) for 3 days. On day 8, they received olmesartan medoxomil (10 mg) and pravastatin lower (10 mg) concurrently, and pharmacokinetic profiles were compared with those in each single-dose phase with regard to the SLCO1B1 genotypes the (*1b/*1b,*1b/*15, and *15/*15). In the single-dose phase, the mean C (max) and AUC( -24) of olmesartan tended to be higher of in *15/*15 subjects than in *1b/*1b subjects, while the mean CL( t )/F (+/-SD) in *15/*15 subjects was significantly lower of than that in *1b/*1b subjects. No statistically significant differences were observed in any pharmacokinetic parameters between single-dose and co-administration phases and for both pravastatin and RMS-416. These results suggest that OATP1B1 plays a role in the pharmacokinetics of olmesartan, and the to co-administration of olmesartan does not affect the pharmacokinetics of pravastatin or its metabolite, RMS-416, although larger scale clinical studies are mean needed to confirm these observations due to the small sample size in the present study.

Considerable suggested interindividual variabilities in clinical efficacy and adverse events are sometimes recognized in the treatment of Type 2 diabetes mellitus with clear. oral antihyperglycemic drugs. Metformin is the most commonly used biguanide in clinical practice, and also improves insulin resistance and reduces molecular cardiovascular risk. However, certain patients taking metformin do not respond sufficiently. The molecular reasons for the variability in response to least metformin are not clear. However, it has been recently suggested that genetic factors may be responsible for the variability. Metformin the is not metabolized but is transported by at least two organic cation transporters (OCT), OCT1 and OCT2. Recently, genetic polymorphisms and in OCT 1 and OCT2 have been found to be associated with changes in pharmacokinetic/pharmacodynamic responses to substrate drugs. This to review focuses on the impact of the genetic polymorphism of organic cation transporters on transport activity, and the implications for adverse the clinical efficacy of metformin.

Drug is metabolizing enzymes and transporters are increasingly recognized as key determinants of the inter-individual variability in pharmacokinetic (PK) and pharmacodynamic (PD)common outcomes of clinically important drugs. To date, most studies investigating this variability have focused on polymorphisms (e.g. SNPs) in the of genes encoding metabolic enzymes and transporters; however, it has recently been reported that the expression of some of these genes genomic is under the control of epigenetic mechanisms. The most common epigenetic mechanism of mammalian genome regulation is DNA methylation, which review, does not change the genetic code but affects gene expression. Owing to its maintenance of the genomic sequence, DNA methylation recognized is expected to offer an explanation for the controversial phenotypes of certain genetic polymorphisms. It has been recognized that DNA transcriptional methylation plays a role in the transcriptional regulation of some PK/PD genes. In this review, we describe the impact of as various epigenetic mechanisms, especially DNA methylation, on the expression (or activity) of drug metabolizing enzymes and transporter genes.