Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
Volume 28 , Issue 6
Showing 1-12 articles out of 12 articles from the selected issue
Editorial
Regular Articles
  • Christine E. DUNNE, Jennifer L. BUSHEE, Upendra A. ARGIKAR
    2013 Volume 28 Issue 6 Pages 453-461
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: April 23, 2013
    JOURNALS FREE ACCESS
    Supplementary material
      Bromopride (BRP) has been utilized clinically for treatment of nausea, vomiting and gastro-intestinal motility disorders. The pharmacokinetics of BRP have been characterized in dogs and humans; however, the metabolic profile of BRP has not been well studied. The present study was aimed at better understanding BRP metabolism across species. We investigated biotransformation of BRP in mouse, rat, rabbit, dog, monkey, and human hepatocytes with the help of LC-MSn and accurate mass measurement. Mice, rats, dogs, and monkeys are relevant in drug discovery and development as pre-clinical species to be compared with humans, whereas rabbits were efficacy models for BRP. Overall, twenty metabolites of BRP were identified across hepatocytes from the six species. Monkeys offered the most coverage for humans, in terms of number of metabolites identified. Interestingly, M14, an N-sulfate metabolite of BRP, was identified as a human-specific metabolite. BRP metabolism had only been reported in dog plasma and urine, historically. Our investigation is the first documentation of in vitro metabolism of BRP in the six species reported here. Metabolites M1, M2, M4–M10, M12, M13, and M15–M20 have not been previously reported. In summary, this report documents seventeen metabolites of BRP for the first time, thus providing a deeper insight into the biotransformation of BRP.
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  • Min-Jung KIM, Jae-Won LEE, Kyung-Suk OH, Chang-Soo CHOI, Kwang Hee KIM ...
    2013 Volume 28 Issue 6 Pages 462-467
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: April 30, 2013
    JOURNALS FREE ACCESS
      The tyrosine kinase inhibitor nilotinib was examined for its inhibition of cytochrome P450s (CYPs) in human liver microsomes and in human CYPs expressed in a baculovirus-insect cell system. Nilotinib demonstrated preferential inhibition of CYP2C8-mediated paclitaxel 6α-hydroxylation, rosiglitazone hydroxylation and amodiaquine N-deethylation in human liver microsomes, with IC50 values of 0.4, 7.5 and 0.7 µM, respectively. The IC50 value of nilotinib for paclitaxel 6α-hydroxylation was 20-fold lower than that of the other five tyrosine-kinase inhibitors tested. Nilotinib appears to display competitive inhibition against paclitaxel 6α-hydroxylation and amodiaquine N-deethylation, with estimated mean Ki values of 0.90 and 0.15 µM in human liver microsomes and 0.10 and 0.61 µM in recombinant human CYP2C8, respectively. These results are consistent with those of molecular docking simulations, where paclitaxel could not access the CYP2C8 catalytic site in the presence of nilotinib, but the binding of midazolam, a substrate of CYP3A4, to the catalytic site of CYP3A4 was not affected by nilotinib. The demonstrated inhibitory activity of nilotinib against CYP2C8 at concentrations less than those observed in patients who received nilotinib therapy is of potential clinical relevance and further in vivo exploration is warranted.
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  • Xu YANJIAO, Zhang CHENGLIANG, Li XIPING, Wu TAO, Ren XIUHUA, Liu DONG
    2013 Volume 28 Issue 6 Pages 468-474
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: May 07, 2013
    JOURNALS FREE ACCESS
      Human carboxylesterase (CES) 1A and CES2, two major forms of human CES, dominate the pharmacokinetics of most prodrugs such as imidapril and irinotecan (CPT-11). Antihypertensive drugs are often prescribed for clinical therapy concurrently with others. Moreover, two or more antihypertensive drugs are ubiquitously combined. The influences of antihypertensive drugs on the activity of CES remain undefined. In the present study, the inhibitory effects of 17 antihypertensive drugs on the CES1A1 and CES2 activities were evaluated. Imidapril and CPT-11 were used as substrates and cultured with liver microsomes in vitro. The imidapril hydrolase activities by recombinant CES1A1 and human liver microsomes (HLM) were intensely inhibited by telmisartan and nitrendipine (Ki = 0.49 ± 0.09 and 1.12 ± 0.39 µM for CES1A1, 1.69 ± 0.17 µM and 1.24 ± 0.27 µM for HLM, respectively). However, other drugs did not exert strong inhibition. The enzyme hydrolase activity of recombinant CES2 was substantially inhibited by diltiazem and verapamil (Ki = 0.25 ± 0.02 and 3.84 ± 0.99 µM, respectively). Hence, diltiazem, verapamil, nitrendipine and telmisartan may attenuate the drug efficacy of catalyzed prodrugs by changing the activities of CES1A1 and CES2.
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  • Mitsuhiro NISHIHARA, Yuto HIURA, Naohiro KAWAGUCHI, Junzo TAKAHASHI, S ...
    2013 Volume 28 Issue 6 Pages 475-484
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: May 07, 2013
    JOURNALS FREE ACCESS
      Recently, genotyping in clinical studies has revealed that UGT2B15 genetic polymorphism has an influence on the clinical pharmacokinetics of sipoglitazar. In this study, the UGT responsible for sipoglitazar was retrospectively identified by in vitro analysis. A study using UGT-expressing supersomes revealed that sipoglitazar glucuronidation was more extensively catalyzed by UGT1A1, 1A3, 1A6, 2B4, and 2B15 than by other UGTs. Enzyme kinetic studies for sipoglitazar glucuronidation and recent findings related to mRNA expression analysis of UGTs narrowed the involved isoforms down to UGT1A1 and UGT2B15 among these five human UGTs. In a correlation study between sipoglitazar glucuronidation and UGT isoform-specific activities, the glucuronidation of S-oxazepam, a specific substrate for UGT2B15, strongly correlated with that of sipoglitazar, as compared with that of β-estradiol, a representative UGT1A1 substrate. The analysis of the species difference strengthens the possibility of UGT2B15 rather than that of UGT1A1. These in vitro findings indicate that UGT2B15 is principally responsible for sipoglitazar glucuronidation. Moreover, the UGT2B15*2 mutation significantly increased the Km value of sipoglitazar in the kinetic analysis using recombinant His-tag UGT2B15*1- or *2-membrane fractions. These results show that sipoglitazar is a good example to elucidate the relationship between phenotype and genotype for UGT2B15 from in vitro analysis.
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  • Yusuke TANAKA, Ryoichi WAKI, Shunji NAGATA
    2013 Volume 28 Issue 6 Pages 485-490
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: April 30, 2013
    JOURNALS FREE ACCESS
      It is well known that large differences exist in the bioavailability of orally administered drugs between species. Dissolution is the first step in the oral absorption of solid drugs. In this study, we measured the in vivo luminal concentrations of griseofulvin (GF) and albendazole (AZ), Biopharmaceutics Classification System (BCS) class II drugs, and the GF fraction absorbed (Fa) in rats. Then, we compared the GF Fa in rat with that in other species reported previously to evaluate differences in drug dissolution and oral absorption. The Fa of GF has been reported to decrease from 80% to 40% with an increase in the oral dose in dogs and humans, because the rate-limiting step for absorption shifts from dissolution to solubility. However, such non-linearity was not observed in rats that were administered doses in the same ranges as those in humans, and the Fa values in rats were higher than those in dogs or humans. The in vivo luminal concentration of GF after oral administration in rats was much higher than the saturated solubility of GF in fasted-state simulated dog (FaSSIFdog) or human intestinal fluid (FaSSIFhuman). Furthermore, oral administration of AZ showed similar tendencies of interspecies differences in dissolution and oral absorption.
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  • Kazuya ISHIDA, Asuka HORIE, Maki NISHIMURA, Masato TAGUCHI, Nozomu FUJ ...
    2013 Volume 28 Issue 6 Pages 491-496
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: May 28, 2013
    JOURNALS FREE ACCESS
      We previously reported that renal function is partly responsible for the interindividual variability of the pharmacokinetics of bisoprolol. The aim of the present study was to examine the variability of bioavailability (F) of bisoprolol in routinely treated Japanese patients and intestinal absorption characteristics of the drug. We first analyzed the plasma concentration data of bisoprolol in 52 Japanese patients using a nonlinear mixed effects model. We also investigated the cellular uptake of bisoprolol using human intestinal epithelial LS180 cells. The oral clearance (CL/F) of bisoprolol in Japanese patients was positively correlated with the apparent volume of distribution (V/F), implying variable F. The uptake of bisoprolol in LS180 cells was temperature-dependent and saturable, and was significantly decreased in the presence of quinidine and diphenhydramine. In addition, the cellular uptake of bisoprolol dissolved in an acidic buffer was markedly less than that dissolved in a neutral buffer. These findings suggest that the rate/extent of the intestinal absorption of bisoprolol is another cause of the interindividual variability of the pharmacokinetics, and that the uptake of bisoprolol in intestinal epithelial cells is highly pH-dependent and also variable.
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  • Ryoko YUMOTO, Sayuri SUZUKA, Saori NISHIMOTO, Junya NAGAI, Mikihisa TA ...
    2013 Volume 28 Issue 6 Pages 497-503
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: May 28, 2013
    JOURNALS FREE ACCESS
      The clearance of albumin from the alveolar space is a critical process in the recovery from edema. In this study, we investigated the effect of poly(amino acid)s such as poly-l-ornithine (PLO) on albumin uptake in the cultured lung epithelial cell line A549. FITC-albumin uptake as well as cell surface binding was markedly stimulated by co-incubation with PLO, and there was a good correlation between them. After being taken up by A549 cells, FITC-albumin was predominantly targeted to lysosomes. Interestingly, pretreatment of A549 cells with PLO further stimulated FITC-albumin uptake, even in the absence of PLO in the uptake buffer. FITC-albumin uptake in the presence of PLO was inhibited by a metabolic inhibitor, clathrin-mediated endocytosis inhibitors, and a macropinocytosis inhibitor, indicating the involvement of clathrin-mediated endocytosis and/or macropinocytosis. The effect of PLO on FITC-albumin clearance was also examined in an in vivo pulmonary administration method in rats, and co-administration of PLO enhanced fluorescence elimination from the lungs. These findings suggest that pulmonary administration of poly(amino acid)s such as PLO is a possible strategy for enhancing albumin clearance from the alveolar space, and thereby facilitating the recovery from pulmonary edema.
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  • Kenji IKEMURA, Erika NAKAGAWA, Tomohiko KURATA, Takuya IWAMOTO, Masahi ...
    2013 Volume 28 Issue 6 Pages 504-509
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: June 18, 2013
    JOURNALS FREE ACCESS
      The renal tubular secretion of cationic drugs is dominated by basolateral organic cation transporter 2 (rOCT2/SLC22A2) and luminal multidrug and toxin extrusion 1 (rMATE1/SLC47A1). Little is known about the variation in the expression of these renal transporters after liver ischemia-reperfusion (I/R) injury. Here, we examined the pharmacokinetics of a cationic drug, cimetidine, and renal rOCT2 and rMATE1 levels as well as their regulation after liver I/R. Rats were subjected to 60 min of liver ischemia followed by 12 h of reperfusion. The antioxidant Trolox® was administered intravenously 5 min before reperfusion. The systemic and tubular secretory clearances of cimetidine (78% and 55%) as well as renal rOCT2 and rMATE1 levels (67% and 61%) in I/R rats were decreased compared with those in sham-operated rats, respectively. However, the renal tissue-to-plasma concentration ratio but not the renal tissue-to-urine clearance ratio of cimetidine was decreased after liver I/R. Moreover, Trolox prevented the decreases in renal rOCT2 levels and systemic clearance of cimetidine after liver I/R. These results demonstrate that liver I/R decreases the tubular secretion of cimetidine, mainly because of the decreased rOCT2 level in the kidney, and that oxidative stress should be responsible in part for decreased renal rOCT2 after liver I/R injury.
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Notes
  • Yasuharu NAKANISHI, Hiroyuki YAMASHITA, Tsuyoshi YOSHIKAWA, Takeshi TO ...
    2013 Volume 28 Issue 6 Pages 510-513
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: May 07, 2013
    JOURNALS FREE ACCESS
    Supplementary material
      Cynomolgus macaques, used in drug metabolism studies due to their evolutionary closeness to humans, are mainly bred in Asian countries, including Cambodia, China, and Indonesia. Cytochromes P450 (P450s) are important drug-metabolizing enzymes, present in the liver and small intestine, major drug metabolizing organs. Previously, our investigation did not find statistically significant differences in hepatic P450 metabolic activities measured in cynomolgus macaques bred in Cambodia (MacfaCAM) and China (MacfaCHN). In the present study, P450 metabolic activity was investigated in the small intestine of MacfaCAM and MacfaCHN, and cynomolgus macaques bred in Indonesia (MacfaIDN) using P450 substrates, including 7-ethoxyresorufin, coumarin, bupropion, paclitaxel, diclofenac, S-mephenytoin, bufuralol, chlorzoxazone, and testosterone. The results indicated that P450 metabolic activity of the small intestine was not statistically significantly different (<2.0-fold) in MacfaCAM, MacfaCHN, and MacfaIDN. In addition, statistically significant sex differences were not observed (<2.0-fold) in any P450 metabolic activity in MacfaCAM as supported by mRNA expression results. These results suggest that P450 metabolic activity of the small intestine does not significantly differ statistically among MacfaCAM, MacfaCHN, and MacfaIDN.
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  • Shingen MISAKA, Keisuke KAWABE, Satomi ONOUE, José Pablo WERBA, ...
    2013 Volume 28 Issue 6 Pages 514-518
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: May 21, 2013
    JOURNALS FREE ACCESS
      Effects of green tea extract (GTE) on the activity of cytochrome P450 (CYP) enzymes and pharmacokinetics of simvastatin (SIM) were investigated in rats. Inhibitory effects of GTE on CYP3A activity were investigated in rat hepatic microsomes (RHM) using midazolam (MDZ) 1′-hydroxylation as a probe reaction. SD female rats received a single oral dose of GTE (400 mg/kg) or troleandomycin (TAO, a CYP3A selective inhibitor, 500 mg/kg), followed 30 min later by SIM (20 mg/kg). Plasma concentrations of SIM and its active metabolite, simvastatin acid, were determined up to 6 h after the SIM administration using LC/MS/MS. In RHM, GTE inhibited MDZ 1′-hydroxylation with IC50 and Kiapp values of 12.5 and 18.8 µg/mL, respectively, in a noncompetitive manner. Area under plasma concentration-time curves for SIM in the GTE and TAO groups were increased by 3.4- and 10.2-fold, respectively, compared with the control. The maximum concentrations of SIM were higher in the GTE (3.3-fold) and TAO (9.5-fold) groups. GTE alters the pharmacokinetics of SIM, probably by inhibiting intestinal CYP3A.
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SNP Communication
  • Isa CAVACO, Francis Wanak HOMBHANJE, José Pedro GIL, Akira KANE ...
    2013 Volume 28 Issue 6 Pages 519-521
    Published: 2013
    Released: December 25, 2013
    [Advance publication] Released: May 07, 2013
    JOURNALS FREE ACCESS
      The diverse cultural and social habits of the Papua New Guinea (PNG) population include betel quid chewing and more recently smoking. The formation of DNA adducts from betel quid is mediated by the cytochrome P450 (CYP) enzymes, including CYP1A2. The tobacco smoke compounds can induce CYP1A2. The transcription factor AhR (aryl hydrocarbon receptor) is involved in the regulation of CYP1A2 expression. AhR activity is itself regulated by other transcription factors, including the aryl hydrocarbon receptor repressor (AhRR). The AhRR Pro185Ala (rs2292596; 565C>G) minor allele was recently associated with a lower AhR repressor activity, leading to a higher CYP1A2 inducibility. We investigated AhRR Pro185Ala SNP in the East Sepik populations in PNG and found a high frequency of 53.4% of the minor allele, significantly different from other Asian populations. We can hypothesize that a high frequency of the AhRR SNP can be a risk factor in the incidence of oral cancer and other neoplasias in PNG due to higher inducibility of CYP1A2. The potential role of AhRR pharmacogenetics in the risk of developing cancers associated with betel quid chewing and smoking should be addressed and clarified in future epidemiological studies in PNG.
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