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Background: The Vav family of Rho/Rac guanosine nucleotide exchange factors comprises three members in mammalian cells. Vav3 enhances androgen receptor (AR) activity during progression to androgen independence in prostate cancer. We examined Vav3 small interfering RNA (siRNA) effects on cell proliferation and apoptosis in docetaxel-treated LNCaP cells under chronic hypoxia (LNCaPH). Methods: We examined individual and combined effects of Vav3 siRNA (si-Vav3) and docetaxel on cell growth and apoptosis under chronic hypoxia by cell proliferation, flow cytometric, DNA fragmentation, and immunoblot analyses. To clarify the molecular basis of si-Vav3- and docetaxel-induced apoptosis, we analyzed alterations in phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulate kinase (ERK), c-jun N-terminal kinase (JNK), and AR pathways using kinase inhibitors in LNCaPH cells. The effects of si-Vav3/atelocollagen complex alone or in combination with docetaxel were assessed on xenografts in nude mice by tumor growth delay. Results: Vav3 overexpression was observed in LNCaPH compared with the expression under normoxia. Interrupting Vav3 signaling using siRNA enhanced docetaxel-induced cell growth suppression compared with that induced by docetaxel alone by inhibition of Akt and ERK phosphorylation, resulting in AR phosphorylation inhibition. In addition to increased B-cell lymphoma 2 (Bcl-2) phosphorylation through JNK signaling in response to docetaxel, si-Vav3 enhanced docetaxel-induced apoptosis, as characterized by the accumulation of sub-G1 phase cells and DNA fragmentation, through Bcl-xL/Bcl-2-associated death promoter (Bad) dephosphorylation, resulting in increased caspase-9, caspase-3, and cleaved poly(ADP-ribose) polymerase activation. Xenograft tumor growth was slightly inhibited by si-Vav3/atelocollagen complex injection and combined use of si-Vav3/atelocollagen complex and docetaxel produced a greater effect than docetaxel alone. Conclusions: Interrupting Vav3 signaling enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia by inhibiting the PI3K/Akt, ERK, and AR signaling pathways. Therapy targeting Vav3 in combination with docetaxel may have practical implications for managing castration-resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Adrenomedullin (ADM) is a 52-amino acid peptide with a variety of physiologic functions such as immunomodulating activity, direct bactericidal activity, maintenance of renal homeostasis, and vasodilatory activity. Midregional proADM (MR-proADM) is derived from a larger 185-amino acid precursor peptide, prepro-adrenomedulin (preproADM), by posttranslational processing. It is suggested to be co-synthesized with ADM in equimolar amounts and has the advantages over ADM in having a longer half-life, no bioactivity, and no binding to protein. Therefore, MR-proADM serves as a surrogate for ADM secretion. In this study, we attempted to develop an enzyme immunoassay (EIA) for quantifying MR-proADM-like immunoreactive substance (IS), which is applicable for monitoring plasma MR-proADM levels. By using β- d-galactosidase-labeled preproADM(83-94) as a marker antigen, anti-rabbit IgG-coated immunoplate as a bound/free separator, and 4-methylumbelliferyl- β- d-galactopyranoside as a fluorogenic substrate, a sensitive and specific EIA was developed for the quantification of MR-proADM-IS in human plasma. The lower limit of quantification was 0.032 pmol/well, and the steep competitive inhibition EIA calibration curve obtained was linear between 0.16 and 10 nmol/L. By using human plasma samples containing 0.2 and 2.0 nmol/L of MR-proADM, the interassay coefficients of variation (reproducibility) were 10.78% and 8.83%, respectively, and intraassay coefficients were 3.91% and 7.81%. Plasma MR-proADM-IS level was significantly higher in patients with chronic renal failure (1.39 ± 0.50 nmol/L) compared with healthy subjects (0.19 ± 0.07 nmol/L). These results suggest that our EIA may be useful to evaluate plasma MR-proADM levels as a biomarker in various clinical settings. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aims To examine the effects of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) on the myogenic differentiation of human urethral rhabdosphincter (RS) satellite cells. Methods Human RS was obtained from patients undergoing radical prostatectomy for prostate cancer. Selectively cultured RS satellite cells, transfected with temperature sensitive simian virus-40 T antigen (ts-SV40 Tag) to extend their lifespan, were cultured at 33°C, and then incubated at 39°C to induce myogenic differentiation. Varying concentrations of HGF and IGF-1 were added to the differentiation medium. Inactivation of SV40 Tag and evaluations of myogenic differentiation were examined by immunocytochemistry, western blotting and real-time RT-PCR. Results At 39°C, ts-SV40 Tag-transfected RS satellite cells slowly proliferated, fused to form multinucleated myotubes, and expressed myosin heavy chain (MHC) in association with the temperature-dependent inactivation of SV40 Tag. IGF-1 significantly accelerated the MHC expression in a dose-dependent fashion through activation of the PI3-kinase pathway. Conversely, HGF did not promote MHC expression due a reduction in phosphorylation of both the MAP-kinase and the PI3-kinase pathways, a pattern of response different than the response of proliferating RS satellite cells to HGF. Conclusions HGF did not induce myogenic differentiation of RS satellite cells. Conversely, IGF-1 promoted myogenic differentiation of RS satellite cells via the PI3-K pathway likewise proliferating RS satellite cells. These findings may be useful for developing novel techniques for regenerating the human RS to treat urinary incontinence. Neurourol. Urodynam. 29:470-475, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

A novel point mutation in a patient with vascular type Ehlers-Danlos syndrome is herein reported. The patient experienced pneumothorax and multiple arterial troubles during the past 10 years. The patient’s hand skin was atrophic, and a paper-like atrophic scar was seen. The collagen microfibrils from the patient’s skin demonstrated irregular contour, electron density variegation, and smaller, irregular fibril diameters. The patient’s fibroblasts produced apparently much less type III collagen comparing with control. A skipping of exon 24-originated sequences of the patient’s mRNA of type III collagen was proved. A single base pair mutation of thymine to guanine at the second position of the intron 24 of COL3A1 was finally found. This is the first report of the mutation of the second position of exon 24 of COL3A1. [ABSTRACT FROM AUTHOR]

Chicken primordial germ cells (PGCs) dynamically migrate towards the prospective gonadal area through the germinal crescent region and bloodstream at early embryonic stages. To date, chicken PGCs have been mainly identified by histochemical and immunohistochemical methods or by their morphological characteristics. However, their origin, migration and differentiation are not fully understood because of the lack of specific PGC molecular markers. Here, we have isolated the chicken dead end homologue (CDH) in order to clone its full-length cDNA with an open reading frame of 329 amino acids. The RNA-binding motif present in CDH at amino acids 54–133 was highly homologous to those in the dead end proteins of human, mouse and Xenopus. The temporal and spatial distribution of PGCs was also investigated by in situ hybridization (ISH) on whole-mount embryos with CDH cRNA as a probe. Chicken embryos from stage X to stage 20 were subjected to ISH. The hybridized samples were then sectioned to analyse the translocation of PGCs. CDH-positive cells could be counted from stage X to stage 4, with minimally 30 cells at the blastderm and approximately 260 cells at the germinal crescent. Thus, specific expression of CDH mRNA has been established in chicken PGCs located at the blastderm, germinal crescent and prospective gonadal area by ISH and reverse transcription/polymerase chain reaction. We conclude that isolated CDH is specifically expressed in chicken PGCs during embryogenesis. [ABSTRACT FROM AUTHOR]

To investigate the precise modality of association between SAA1 gene polymorphisms and the development of AA amyloidosis in patients with rheumatoid arthritis (RA), Japanese patients with RA ( n = 153), among whom 29 were histologically diagnosed as having amyloidosis, were genotyped for three single nucleotide polymorphisms (SNPs), C-13T, C2995T, and C3010T, in the SAA gene. Pairwise linkage disequilibrium coefficients between each pair of SNPs were calculated and estimated haplotype frequencies were compared between patients with and without amyloidosis. Possible associations between these SNPs and amyloidosis were analyzed by a case–control study and by the Kaplan–Meier method, in which the endpoint was defined as the time of diagnosis of AA amyloidosis. The -13T and 2995C alleles, which were in a tight linkage disequilibrium, were more frequent in the patients with amyloidosis, and the groups with the -13TT and 2995CC genotype had worse survival curves than patients without these genotypes, whereas C3010T was not associated with amyloidosis. Moreover, the haplotype containing − 13C and 2995T was found to be protective. Both C-13T and C2995T were associated with the development of amyloidosis. Examining both polymorphisms may be more useful than examining only one of them for estimating the risk of the development of amyloidosis. [ABSTRACT FROM AUTHOR]

Myostatin (GDF-8) is known to negatively regulate skeletal muscle mass in myogenesis, but few studies have been conducted on the function of endogenous GDF-8 in primary myoblasts. The present study was performed to assess the function of GDF-8 by RNA interference using primary culture of chicken embryonic myoblasts in which myoblasts were differentiated into myotubes. An active form of small interfering RNA (siRNA-1) targeting GDF-8 mRNA was introduced into myoblasts, and an inactive form of siRNA (siRNA-2) was used as a negative control. GDF-8 transcript level was significantly reduced 24 h after the introduction of siRNA-1 to 25% of the control, whereas a 52-kDa GDF-8 precursor was reduced to 45% of the control at 48 h. However, siRNA-2 did not decrease GDF-8 transcript level. When GDF-8- mediated promoter activity was measured chronologically by means of a pGL(CAGA) 10-constructed luciferase reporter assay, a concomitant change in activity was initiated after 24 h. The activity rapidly decreased 30 h after siRNA-1 introduction, whereas high activity was maintained at 30-42 h in the control and siRNA-2-treated myoblasts. Myogenic factors such as MyoD and p21, but not myogenin, were altered after 72 h. Cell fusion of the multinucleated myotubes was delayed by the siRNA-1 introduction, and myotubes with aggregated nuclei were shorter and wider. These results strongly suggest that deficiency of GDF-8 delays cell differentiation and causes great alterations in the cellular morphology of chicken embryonic myotubes. [ABSTRACT FROM AUTHOR]

Purpose: We clarified the contractile properties of human male periurethral striated muscle fibers to better understand how the rhabdosphincter and the levator ani maintain urinary continence. Materials and Methods: Muscle specimens were obtained from 52 male patients who underwent radical prostatectomy or radical cystectomy. The specimens were frozen in liquid nitrogen. Frozen sections (10 μm thick) were stained with myofibrillar ATPase at different pH values (pH 4.2, 4.6 and 10.6), and evaluated for quantitative parameters and fiber type distribution. Myosin heavy chain analysis was performed using SDS-PAGE. Results: Of all 52 cases 37 provided specimens that could be divided into the 2 major fiber types, type 1 (slow twitch) and type 2 (fast twitch). Although type 1 muscle fibers were predominant in RS and LA muscle groups (RS 69.6 ± 2.7%, LA 67.0 ± 2.0%), mean muscle fiber size was significantly smaller in RS (mean area 906 ± 86 μm2) than in LA (mean area 2,967 ± 170 μm2) (p <0.0001). In 11 specimens type 2 muscle fibers could be subdivided into types 2A (fast fatigue resistant) and 2B (fast fatigable). Type 2A fibers were significantly more prevalent than type 2B fibers (p <0.05). Likewise, MHC analysis of these 11 specimens found a significantly higher percentage of fiber type 2A expression products (MHC 2A) than of fiber type 2B expression products (MHC 2X) (p <0.05). Conclusions: RS and LA contribute to urinary continence mechanism by slow contraction. Moreover, the smaller mean size of muscle fibers in RS suggests more fatigue resistance compared with muscle fibers in LA because small fibers have a shorter diffusion distance for metabolic substrates. These results should help contribute to a more detailed understanding of the function of periurethral striated muscles in the human male. [Copyright &y& Elsevier]

Background. Monocyte chemoattractant protein (MCP)-1 is closely related to the pathogenesis of the progression of various chronic renal diseases, including IgA nephropathy (IgAN), through its chemoattractant effect on macrophages. However, the correlation of MCP-1 gene polymorphism with the long-term prognosis of Japanese patients with IgAN has not been clearly determined yet. Methods. We investigated 277 Japanese patients diagnosed with IgAN based on renal biopsy to clarify the association between the progression of IgAN and MCP-1 gene polymorphism at position A-2518G, which regulates the transcription of the MCP-1 gene. Results. The incidence of endstage renal disease was signifi- cantly higher in patients with the AA genotype (47.1%) compared to those with the AG (24.1%) or GG (27.4%) genotype (P = 0.024). Moreover, Kaplan-Meier analysis revealed that the AA genotype significantly facilitated the progression of renal disease (log rank; P = 0.0029), and Cox proportional hazards regression model analysis showed that the AA genotype represented a 2.058-fold risk for the progression of renal disease (P = 0.026) compared to the AG/ GG genotype. However, when the patients were treated with angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker, or corticosteroid, homozygosity for the -2518A allele was not associated with a higher rate of incidence of endstage renal disease. Serum MCP-1 levels were higher although not significantly so, in the patients with IgAN possessing the AA genotype. Conclusions. The AA genotype at MCP-1 -2518 was an independent risk factor for the progression of renal disease in Japanese patients with IgAN, and was closely associated with renal survival. [ABSTRACT FROM AUTHOR]

2-Methoxyestradiol (2-ME) has potent antiproliferative effects on cancer cells. Its utility alone or in combination with other therapies for treating prostate cancer, however, has not been fully explored. Androgen-dependent and independent human prostate cancer cells were examined in vivo for their response to combination therapy. Efficacy was assessed by terminal deoxynucleotide transferase--mediated dUTP nick-end labeling assay and measuring microvessel density (MVD) in excised tumors. Animals harboring hormone-dependent tumors treated with 2-ME alone, androgen deprivation therapy alone, or the combination of the two had a 3.1-fold, 5.3-fold, and 10.1-fold increase in apoptosis, respectively. For hormone-independent tumors, treatment with 2-ME resulted in a 2.43-fold increase in apoptosis and a 73% decrease in MVD. 2-ME was most effective against hormone-dependent tumors in vivo and combination therapy resulted in a significant increase in efficacy compared to no treatment controls and trended toward greater efficacy than either 2-ME or androgen deprivation alone. Combination therapy should be investigated further as an additional therapeutic option for early prostate cancer. [ABSTRACT FROM AUTHOR]

TGF-β gene is expressed at various developmental stages and its principle role may be an involvement in organogenesis. The present study was performed to investigate the temporal expression of these TGF-β isoforms in the developing limb of White Leghorn Chicken, Gallus gallus (L., 1758). TGF-β isoforms were expressed in the developing limb as revealed by whole-mount in situ hybridization, but each showed a different pattern of expression. TGF-β2 was the dominant isoform compared with the other two isoforms. TGF-β2 first appeared along the proximodistal axis of the limb at stage 24 and condensed at the tip at stage 26. At stages 29–31, expression appeared in digits and then was extended to the interdigital spaces. A weak signal for TGF-β3 was first shown in the developing limb at stage 26, but there was no interdigital expression, unlike for TGF-β2. TGF-β4 was expressed in the developing limb at stage 26 and only in the interdigital spaces at stage 29. Reverse transcription – polymerase chain reaction analysis also showed that the transcript levels of TGF-β isoforms, especially TGF-β2, drastically increased at stage 29. These results suggest that TGF-β isoforms, with their patterns of expression, are specific regulatory factors that participate in limb development and digit morphogenesis. [ABSTRACT FROM AUTHOR]

Pretreatment serum FGF-23 levels predict the efficacy of calcitriol therapy in dialysis patients.Background.The predictor for the result of calcitriol therapy would be useful in the clinical practice of secondary hyperparathyroidism. Fibroblast growth factor-23 (FGF-23) is a newly found circulating phosphaturic factor. Its circulating level is elevated in uremia.Methods.Dialysis patients with plasma intact parathyroid hormone (iPTH) levels greater than 300 pg/mL were included in the study. Calcitriol was intravenously injected three times a week. The patients whose plasma iPTH levels dropped below 300 pg/mL within 24 weeks were defined as those who had been successfully treated. A sandwich enzyme-linked immunosorbent assay (ELISA) system that detects human FGF-23 was applied.Results.Sixty-two patients were analyzed. The pretreatment FGF-23 levels were related to the iPTH levels, calcium× phosphate product levels, and history of active vitamin D therapy. The pretreatment FGF-23, iPTH, and calcium levels were lower in the patients who would be successfully treated with calcitriol. A logistic regression study revealed that the pretreatment iPTH and FGF-23 levels significantly affected the therapy results. Analyses using a receiver-operated curve revealed that FGF-23 was the best screening test for identifying patients with future refractory response to calcitriol therapy. The treatment would be successful in 88.2% of those with FGF-23≤9860 ng/L and iPTH≤591 pg/mL, while it would be successful in only 4.2% of those with FGF-23>9860 ng/L and iPTH>591 pg/mL.Conclusion.Pretreatment serum FGF-23 levels were a good indicator in predicting the response to calcitriol therapy. The measurement of serum FGF-23 levels, especially in combination with iPTH levels, is a promising laboratory examination for the clinical practice of secondary hyperparathyroidism. [ABSTRACT FROM AUTHOR]

In our search for a new agent, human neutrophil elastase (HNE) inhibitor, for the treatment of acute respiratory failure, we rationally designed and synthesized a series of peptide-based carboxylic acid-containing transition-state inhibitors. The presence of valyl moiety is found to be essential for potent in vitro inhibitory activity and also prevention of an undesirable toxicity. Of these, compound 9m has the most potent in vivo effect on HNE-induced lung hemorrhage in hamsters. [Copyright &y& Elsevier]

The normal development of elastin fibers in the thoracic aorta was studied in fetal, young, and adult monkeys. Tissue was examined by scanning electron microscopy (SEM) after NaOH treatment and by transmission electron microscopy (TEM). The NaOH treatment of fixed tissues effectively removed collagen fibers and enabled three-dimensional visualization of the elastin fibers. In intact fetal aortae, the internal elastic lamina (IEL) was situated immediately beneath the endothelium. This IEL consisted of superficial, longitudinally arranged bundles of elastin fibrils and an underlying solid sheet containing round fenestrations. In neonates, diffuse intimal thickening was observed. In the young and young-adult monkeys, the aortae exhibited intimal thickening with slender but split IEL. One of the most important findings of this study was that elastin fibers in the intimal thickening, as well as smooth muscle cells, ran in a longitudinal fashion. This was in contrast with the elastic laminae of the media which were mainly oriented circumferentially. Subendothelial elastin fibers in this intimal thickening combined with longitudinally arranged microfibrils which formed close associations with endothelial stress fibers. In some adult monkey aortae with well-developed intimal thickening, a complex meshwork of slender elastin fibers was also found beneath the endothelium. The development of the intimal elastin fibers is discussed in relation to hemodynamic forces. [ABSTRACT FROM AUTHOR]

A modified NaOH maceration method for removing extracellular ground substance was applied to scanning electron microscopic (SEM) studies of the mammalian aorta and elastic cartilage. Fixed tissues were freeze-fractured in liquid nitrogen and then immersed in 2 N NaOH solution for 4–6 hr at room temperature. Since this method selectively digested proteoglycans, cellular and fibrous elements were observable clearly under the SEM. The elastic laminae of smooth muscle cells of the aortic tunica media were concealed by fine collagen fibrils, while chondrocytes in the elastic cartilage were encapsulated by a dense network of fine collagen fibrils and branching elastin fibers. [ABSTRACT FROM PUBLISHER]

Lymphoepithelioma-like carcinoma (LELC) in the bladder is uncommon with a reported incidence of 0.4%-1.3% of all bladder carcinomas. In Japan, some occurrences of LELC have been reported in the renal pelvis and ureter but only two in the bladder. A bladder tumor was identified in a 70-year-oldman suffering frommacroscopic hematuria for 2months. Sections of the transurethral tumor resection showed invasive high-grade urothelial carcinoma. The patient was diagnosed with local invasive bladder tumor, and cystectomy with ileal conduit formation was performed. The final pathological evaluation was predominant LELC with urothelial carcinoma. We present a new case of LELC in the bladder and performed a review of all published cases of LELC in the urinary tract to obtain its characteristics and prognostic guide. [ABSTRACT FROM AUTHOR]

Front Cover: Incorporation of Pseudo-complementary Bases 2,6-Diaminopurine and 2-Thiouracil into Serinol Nucleic Acid (SNA) to Promote SNA/RNA Hybridization (Chem. Keywords: acyclic nucleic acid; serinol nucleic acid; pseudo complementary base; 2,6-diaminopurine; 2-thiouracil EN acyclic nucleic acid serinol nucleic acid pseudo complementary base 2,6-diaminopurine 2-thiouracil 1180 1180 1 04/22/20 20200417 NES 200417 B Serinol nucleic acid (SNA) b is promising for nucleic acid-based drugs due to its affinity to RNA. It is thus crucial to suppress self-hybridization for promoting SNA-RNA hybridization. [Extracted from the article]

In higher vertebrates, cephalic neural crest cells (NCCs) form craniofacial skeleton by differentiating into chondrocytes and osteoblasts. A subpopulation of cephalic NCCs, cardiac NCCs (CNCCs), migrates to the heart. However, CNCCs mostly do not yield skeletogenic derivatives, and the molecular mechanisms of this fate restriction remain elusive. We identify a disintegrin and metalloprotease 19 (Adam19) as a position-specific fate regulator of NCCs. Adam19-depleted mice abnormally form NCC-derived cartilage in their hearts through the upregulation of Sox9 levels in CNCCs. Moreover, NCC-lineage-specific Sox9- overexpressing mice recapitulate CNCC chondrogenesis. In vitro experiments show that Adam19 mediates the cleavage of bone morphogenic protein (BMP) type I receptor Alk2 (Acvr1), whereas pharmacogenetic approaches reveal that Adam19 inhibits CNCC chondrogenesis by suppressing the BMP-Sox9 cascade, presumably through processing Alk2. These findings suggest a metalloprotease-dependent mechanism attenuating cellular responsiveness to BMP ligands, which is essential for both the positional restriction of NCC skeletogenesis and normal heart development. • Adam19 mutants exhibit neural crest-derived cardiac cartilage formation • High Sox9 expression in Adam19 −/− -CNCCs induces cardiac cartilage formation • Adam19 mediates proteolytic cleavage of BMP receptor Alk2 • Adam19 suppresses CNCC chondrogenesis by inhibiting the BMP-Sox9 signaling pathway Arai et al. show that metalloprotease Adam19 is essential for proper differentiation of cardiac neural crest cells (CNCCs) in murine embryogenesis. Adam19 suppresses the response of CNCCs to bone morphogenic protein by cleaving its receptor Alk2, thus restricting CNCC skeletogenic potential and preventing cartilage formation in the heart. [ABSTRACT FROM AUTHOR]

Blood concentrations of tacrolimus show large variability among patients and the narrow therapeutic range is related to adverse effects. Therefore, therapeutic drug monitoring is needed for strict management. 13‐O‐Demethyl tacrolimus (13‐O‐DMT) was reported as the major metabolite formed by cytochrome P450 (CYP)3A such as CYP3A5. In previous studies, the best lower limit of quantification (LLOQ) was 0.1 ng/mL for both substances. However, this LLOQ may not be low enough now because the dosage of tacrolimus has decreased in recent years. The purpose of this study was to develop and validate a high‐sensitivity and high‐throughput assay for simultaneous quantification of tacrolimus and 13‐O‐DMT in human whole blood using ultra‐performance liquid chromatography with tandem mass spectrometry (UPLC–MS/MS). Thirty‐five stable kidney transplant recipients receiving tacrolimus were recruited in this study. The calibration curve range was 0.04–40 ng/mL. All calibration samples and quality control samples fulfilled the requirements of the US Food and Drug Administration and the European Medicines Agency guidelines for assay validation. Trough concentrations of tacrolimus and 13‐O‐DMT in 35 stable kidney transplant recipients receiving tacrolimus were within the range of the respective calibration curve. Our novel UPLC–MS/MS method is more sensitive than previous methods for quantification of tacrolimus and 13‐O‐DMT. [ABSTRACT FROM AUTHOR]

The article discusses studies focusing on the outcome of laparoscopic radical cystectomy. Noted is the study by Kanno et al. which analyzes complications of laparoscopic radical cystectomy in cohort patients. Mentioned complications depicted by Hautmann et al. include hydronephrosis and incisional hernia.

Purpose: Recently, several studies have shown that renal failure decreases the metabolic clearance of drugs and the transportation capability of some drug transporters. However, whether organic anion transporting polypeptide (OATP)1B activities decrease in renal failure remains unknown. In this study, we measured plasma concentrations of coproporphyrin-I (CP-I), a specific endogenous OATP1B probe, in patients with end stage renal disease before and after living kidney transplantation and evaluated the effect of renal function on OATP1B activity. Methods: This prospective study recruited 13 patients with end-stage renal disease. Plasma CP-I concentrations were measured before and 7, 14, 30 and 90 days after living kidney transplantation. Results: Plasma CP-I concentrations decreased over time after living kidney transplantation and showed significant difference on day 90 compared with before living kidney transplantation [1.12 ± 0.59 vs 0.65 ± 0.27 ng/mL, p < 0.05 (95% CI of difference − 0.927, −0.013)]. A significant negative correlation was observed between estimated glomerular filtration rate and plasma CP-I concentration (r = −0.30, p < 0.05), suggesting recovery of OATP1B activity with improvement in renal function. Conclusions: OATP1B activity may decrease in renal failure and dose adjustment of OATP1B substrates may be needed in patients with renal failure. [ABSTRACT FROM AUTHOR]