Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
Volume 24 , Issue 5
Showing 1-14 articles out of 14 articles from the selected issue
Editorial
Regular Articles
  • Kohei TOGAMI, Sumio CHONO, Toshinobu SEKI, Kazuhiro MORIMOTO
    2009 Volume 24 Issue 5 Pages 411-417
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
      The distribution characteristics of telithromycin (TEL), a novel ketolide antimicrobial agent, in lung epithelial fluid (ELF) and alveolar macrophages (AMs) were evaluated. In vivo animal experiments, the time-courses of the concentrations of TEL in ELF and AMs following oral administration of TEL solution (50 mg/4 mL/kg) to rats were markedly higher than in plasma, and areas under drug concentration-time curve (AUC) ratios of ELF/plasma and AMs/plasma were 2.4 and 65.3, respectively. In vitro transport experiments, the basolateral-to-apical transport of TEL through model lung epithelial cell (Calu-3) monolayers was greater than apical-to-basolateral transport. Rhodamine123 and verapamil, MDR1 substrates, reduced the basolateral-to-apical transport of TEL. In vitro uptake experiments, the intracellular equilibrated concentration of TEL in cultured AMs (NR8383) was approximately 40 times the extracellular concentration. The uptake of TEL by NR8383 was inhibited by rotenone and FCCP, ATP depletors and was temperature-dependent. These data suggest that the high distribution of TEL to AMs is due to the sustained distribution to ELF via MDR1 as well as the high uptake by AMs themselves via active transport mechanisms.
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  • Mikihisa TAKANO, Yoshifumi OTANI, Minori TANDA, Masashi KAWAMI, Junya ...
    2009 Volume 24 Issue 5 Pages 418-427
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
      Paclitaxel-resistant HepG2 (PR-HepG2) cells were established by long-term exposure of HepG2 cells to paclitaxel and expression and function of efflux (P-glycoprotein, MRP2) and influx (OATP1B3) transporters for paclitaxel were examined to understand the mechanisms underlying the resistance. mRNA expression of P-glycoprotein (P-gp) increased in PR-HepG2 more than in HepG2 cells, while that of MRP2 did not change. Interestingly, mRNA expression of OATP1B3 drastically decreased in PR-HepG2 cells. [3H]Paclitaxel uptake was less in PR-HepG2 than in HepG2 cells and the uptake in both cells increased by metabolic inhibition. The uptake of [3H]paclitaxel and rhodamine 123 increased by verapamil, a P-gp inhibitor. Probenecid, an MRP inhibitor, did not affect [3H]paclitaxel uptake in both cells. Sulfobromophthalein, an OATP1B3 inhibitor, inhibited [3H]paclitaxel uptake in HepG2 but not in PR-HepG2 cells. Cytotoxicity studies showed that the resistance of PR-HepG2 cells to paclitaxel was reversed by verapamil. PR-HepG2 cells showed cross-resistance to doxorubicin, a P-gp substrate, but not to cisplatin. These results indicate that enhanced expression and function of P-gp may be a predominant mechanism of paclitaxel resistance in PR-HepG2 cells and the reduced influx via OATP1B3 may also serve to lower intracellular paclitaxel concentration in cooperation with P-gp-mediated efflux.
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  • Mikio TOMITA, Hisanao KISHIMOTO, Yusuke TAKIZAWA, Masahiro HAYASHI
    2009 Volume 24 Issue 5 Pages 428-437
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
      To analyze the effects of I/R on P-gp function in liver and kidney, biliary and urinary excretions of rhodamine123 as a substrate of P-gp were examined in rats. The effects of reperfusion time on change and recovery of P-gp function were also examined. The biliary and renal clearance of rhodamine123 significantly decreased at 3 hr after reperfusion, but returned to control levels at 24 hr after reperfusion. These results suggest that intestinal I/R-induced decrease in P-gp-mediated biliary and renal excretion of rhodamine123 is litely due to impairment of P-gp-mediated transport ability. The level of P-gp protein in liver decreased and that of iNOS mRNA increased at 3 hr after reperfusion and both levels returned to control levels at 24 hr after reperfusion. No marked change in the levels of P-gp protein and iNOS mRNA was observed in kidney at 3 hr and 24 hr after reperfusion. Thus, decrease in biliary excretion of rhodamine123 would appear due in part to decrease in expression of P-gp, caused by increase in lipid peroxidation levels through iNOS mRNA.
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  • Ami OGURO, Natsuko FUJITA, Susumu IMAOKA
    2009 Volume 24 Issue 5 Pages 438-445
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
      Soluble epoxide hydrolase (sEH) is a xenobiotic-metabolizing enzyme that metabolizes epoxides to produce vicinal diols. Diabetes is a common pathological condition which effects drug metabolism. This study, investigates changes in the levels of sEH in mice with diabetes induced by streptozotocin (STZ). Diabetes reduced the amount of sEH protein in the liver and insulin restored the level of protein. The kidneys are a target of diabetes. Diabetes significantly decreased levels of sEH protein and also mRNA. The distribution of sEH in the kidney was studied with immunostaining. There was distinct staining in the proximal tubules but not in the glomerulus or other regions. Diabetes is characterized by high glucose concentrations that lead to increased production of reactive oxygen species (ROS). High glucose suppressed sEH mRNA and protein expression in Hep3B cells. NADPH oxidase is the main source of ROS generation in high glucose condition. The NADPH oxidase inhibitor, diphenyleneiodonium chloride (DPIC), inhibited decrease in sEH expression at high glucose and hydrogen peroxide suppressed sEH expression. These findings indicate that diabetes reduces sEH expression by inducing ROS and may have important effects on the metabolism of xenobiotics and endogenous substrates of sEH.
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  • Masuhiro NISHIMURA, Shizuo NARIMATSU, Shinsaku NAITO
    2009 Volume 24 Issue 5 Pages 446-450
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
      This study evaluates the induction potency of new drug candidates on mRNA levels of CYP1A2 and CYP3A4 in primary cultures of cryopreserved human hepatocytes. Analysis was performed by quantitative real-time RT-PCR using primers and TaqMan probes. Positive controls for CYP1A2 and CYP3A4 used β-naphthoflavone (β-NF) and rifampicin (Rif), respectively. In the first stage of the study, the lot showing the best induction of mRNA expression CYP1A2 and CYP3A4 from among eight lots of hepatocytes was selected. In the second stage, we evaluated the levels of CYP1A2 and CYP3A4 gene expression in hepatocytes after exposure to eight NO-1886 (ibrolipim) derivatives. A combination of real-time one-step RT-PCR and primary culture of cryopreserved human hepatocytes is suitable for evaluating of induction potency of a large number of new drug candidates.
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  • Yuki IZUWA, Jun-ichi KUSABA, Mizuki HORIUCHI, Tetsuya AIBA, Hiromu KAW ...
    2009 Volume 24 Issue 5 Pages 451-457
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
       A comparative study of altered plasma concentration of quinidine in rats with glycerol- and cisplatin-induced acute renal failure (ARF) was conducted with quinidine used as a positively charged and liver-metabolized therapeutic compound. Although apparent total body clearance of quinidine decreased to 68 and 48% of the normal value in glycerol- and cisplatin-induced ARF rats, respectively, its distribution decreased only in glycerol-induced ARF rats. The plasma unbound fraction of quinidine decreased in glycerol-induced ARF rats, which was not observed in cisplatin-induced ARF rats. The plasma level of α1-acid glycoprotein (AGP) increased in glycerol-induced ARF, but not in cisplatin-induced ARF rats. It is therefore conceivable that the plasma concentration of positively charged and liver-metabolized compounds generally increases due to hepatic elimination suppressed as renal function decreases, but the pharmacokinetic impact of suppressed hepatic elimination is occasionally difficult to observe in some ARF model rats since it may be blurred by the influence of increased plasma AGP level.
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Note
  • Keiko HOSOHATA, Satohiro MASUDA, Atsushi YONEZAWA, Mitsuhiro SUGIMOTO, ...
    2009 Volume 24 Issue 5 Pages 458-463
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
       This study assesses the effects of rabeprazole on the pharmacokinetics of tacrolimus, considering the cytochrome P450 (CYP) 2C19 and CYP3A5 genotypes of living-donor liver transplant patients (native intestine) and their corresponding donors (graft liver). We examined the concentration/dose ratio of tacrolimus in transplant patients treated with (n=17) or without (n=38) rabeprazole at 10 mg/day on postoperative days 22-28. A stratified analysis revealed no significant differences between the control and rabeprazole groups in the median (range) concentration/dose ratio of tacrolimus [(ng/mL)/(mg/day)] for CYP2C19 extensive/intermediate metabolizers [2.71 (1.00-6.15) versus 2.55 (0.96-9.25); P=0.85] and for poor metabolizers [4.92 (2.44-7.00) versus 3.82 (2.00-7.31); P=0.68], respectively. Even based on the classification of CYP2C19 genotypes of donors, no significant difference in the concentration/dose ratio of tacrolimus was found for the two groups (CYP2C19 extensive/intermediate metabolizers, P=0.52; poor metabolizers, P=0.51). The same was observed for CYP3A5*1 carriers (P=0.97 for native intestine; P=0.87 for graft liver) and CYP3A5*3/*3 carriers (P=0.89 for native intestine; P=0.56 for graft liver). These findings suggest a safer dosing and monitoring of tacrolimus coadministered with rabeprazole early on after liver transplantation regardless of the CYP2C19 and CYP3A5 genotypes of transplant patients and their donors.
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SNP Communications
  • Daisuke KANDA, Hitoshi TAKAGI, Yasutsugu KAWAHARA, Yutaka YATA, Tomofu ...
    2009 Volume 24 Issue 5 Pages 464-468
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
      The Dubin-Johnson syndrome (DJS) is an inherited liver disorder characterized by conjugated hyperbilirubinemia and caused by ABCC2 gene mutations resulting in deficiency of multidrug resistance associated-protein 2 (MRP2) function. A 76-year-old woman with serious jaundice was referred to our hospital. She was clinically diagnosed with DJS with hepatic congestion, due to constrictive pericarditis. We analyzed all exons and exon-intron junctions of the ABCC2 gene by DNA sequencing and identified a new large-scale deletion, 1008 bp, including the whole exon 7, as homozygosity. Some mutations in the ABCC2 gene associated with splicing errors have been reported in intronic regions; however, this is a new type of large-scale deletion detectable in the genomic DNA sequence. Severe hyperbilirubinemia is rare in patients with constrictive pericarditis and this case suggests that MRP2 may play a crucial role in compensating for the serum bilirubin in congestive hepatopathy.
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  • Choo Bee LEAN, Edmund Jon Deoon LEE
    2009 Volume 24 Issue 5 Pages 469-474
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
      MCT1(SLC16A1) is the first member of the monocarboxylate transporter (MCT) and its family is involved in the transportation of metabolically important monocarboxylates such as lactate, pyruvate, acetate and ketone bodies. This study identifies genetic variations in SLC16A1 in the ethnic Chinese group of the Singaporean population (n=95). The promoter, coding region and exon-intron junctions of the SLC16A1 gene encoding the MCT1 transporter were screened for genetic variation in the study population by DNA sequencing. Seven genetic variations of SLC16A1, including 4 novel ones, were found: 2 in the promoter region, 2 in the coding exons (both nonsynonymous variations), 2 in the 3′ untranslated region (3′UTR) and 1 in the intron. Of the two mutations detected in the promoter region, the -363-855T>C is a novel mutation. The 1282G>A (Val428Ile) is a novel SNP and was found as heterozygotic in 4 subjects. The 1470T>A (Asp490Glu) was found to be a common polymorphism in this study. Lastly, IVS3-17A>C in intron 3 and 2258 (755)A>G in 3′UTR are novel mutations found to be common polymorphisms in the local Chinese population. To our knowledge, this is the first report of a comprehensive analysis on the MCT1 gene in any population.
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  • Dorothy Su Lin TOH, Seok Hwee KOO, Lie Michael George LIMENTA, Jie Yin ...
    2009 Volume 24 Issue 5 Pages 475-481
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
      The novel organic cation transporter 1 (OCTN1) is a multispecific, bidirectional and pH-dependent organic cation transporter with low carnitine transport activity. It is a transporter of the physiological substance ergothioneine and mediates the transport of a variety of organic cations such as tetraethylammonium, pyrilamine and quinidine. This study identifies genetic variations of the SLC22A4 gene in two distinct ethnic groups of the Singaporean population (n=192) by DNA sequencing. Twenty four genetic variants of SLC22A4, including 14 found to be novel. 16 in the coding exons (10 nonsynonymous and 6 synonymous variations) and 8 in the introns. Among the novel nonsynonymous variations, Arg63His, Arg83Pro, Met344Lys and Ile500Asn were predicted to be functionally significant. These data should provide fundamental and useful information for pharmacogenetic studies on drugs that are substrates of OCTN1 in Asians.
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  • Porntipa KORPRASERTTHAWORN, Wandee UDOMUKSORN, Krongtong YOOVATHAWORN
    2009 Volume 24 Issue 5 Pages 482-485
    Published: 2009
    Released: October 31, 2009
    JOURNALS FREE ACCESS
      The human UDP-glucuronosyltransferase, UGT1A9, catalyzes glucuronidation of various endobiotics and xenobiotics. In this study, we sequenced the promoter and exon 1 regions of the UGT1A9 gene in 93 Thai individuals and identified 7 genetic polymorphisms. The allele frequencies of all 3 novel single nucleotide polymorphisms (SNPs): 454A>G and 455A>C (N152A) and 760C>T (R254X) were 0.005. The other 4 known polymorphisms, -688A>C, -440T>C, -331C>T and -118A(T)10AT (UGT1A9*1b), were identified and found to have frequencies of 0.124, 0.978, 0.968 and 0.532, respectively.
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