Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
Volume 28 , Issue 1
Showing 1-11 articles out of 11 articles from the selected issue
Editorial
Theme Articles: Theme Issue on Clinical Impact and Evidence of the Pharmacokinetics Change
Preface
Reviews
  • Inna Y. GONG, Richard B. KIM
    2013 Volume 28 Issue 1 Pages 4-18
    Published: 2013
    Released: February 25, 2013
    [Advance publication] Released: October 09, 2012
    JOURNALS FREE ACCESS
      There has been remarkable progress during the past decade in understanding of how genetic variations in drug metabolizing enzymes and transporters contribute to observed variation in drug responsiveness. Among drug transporters, the organic anion transporting polypeptide (OATP) class of transporters have proven to be remarkably important to the cellular uptake disposition of a variety of clinically important drugs, particularly in organs such as the intestine and liver; we now know that altered OATP activity may confer reduced efficacy and potentially increased risk of drug-related toxicity. OATP1B1 and OATP1B3 are widely recognized liver-specific members of the family known to modulate the hepatocellular uptake of drugs from the portal vein and thereby modulate systemic exposure and hepatic substrate drug extraction. On the other hand, OATP2B1 and OATP1A2 are expressed on the apical membrane of intestinal enterocytes and though to affect absorption of its drug substrates. Accordingly, genetic variations in these OATP transporters have clinically relevant functional consequences for drug absorption, distribution and excretion, as well as pharmacodynamics response in terms of drug efficacy and toxicity. This article addresses the present evidence of relevance to genetic variations in OATP1B1, OATP1B3, OATP2B1, and OATP1A2 in terms of drug response, efficacy and optimal therapeutics.
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  • Jason A. SPROWL, Rachel A. NESS, Alex SPARREBOOM
    2013 Volume 28 Issue 1 Pages 19-27
    Published: 2013
    Released: February 25, 2013
    [Advance publication] Released: September 18, 2012
    JOURNALS FREE ACCESS
      Several solute carriers and ATP-binding cassette transporters have been implicated in the influx or efflux of platinum-based chemotherapeutic agents such as cisplatin, carboplatin, and oxaliplatin. Given that many of these proteins are highly polymorphic, the genetic status of these proteins could be an important contributor to the extensive interindividual pharmacokinetic variability associated with the clinical use of these agents. In this review article, we provide an updated overview of the various transporters that have shown promise in animal models or patient populations in facilitating the movement of platinum-based agents across cell membranes, and how their function is associated with drug disposition or pharmacodynamic effects.
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  • Takeshi HIROTA, Shunsuke EGUCHI, Ichiro IEIRI
    2013 Volume 28 Issue 1 Pages 28-37
    Published: 2013
    Released: February 25, 2013
    [Advance publication] Released: November 20, 2012
    JOURNALS FREE ACCESS
      Human cytochrome P450 (CYP) is a superfamily of hemoproteins which oxidize a number of endogenous compounds and xenobiotics. The human CYP2C subfamily consists of four members: CYP2C8, CYP2C9, CYP2C18 and CYP2C19. CYP2C9 and CYP2C19 are important drug-metabolizing enzymes and together metabolize approximately 20% of therapeutically used drugs. Forty-two allelic variants for CYP2C9 and 34 for CYP2C19 have been reported. The frequencies of these variants show marked inter-ethnic variation. The functional consequences of genetic polymorphisms have been examined, and many studies have shown the clinical importance of these polymorphisms. Current evidence suggests that taking the genetically determined metabolic capacity of CYP2C9 and CYP2C19 into account has the potential to improve individual risk/benefit relationships. However, more prospective studies with clinical endpoints are needed before the paradigm of “personalized medicine” based on the variants can be established. This review summarizes the currently available important information on this topic.
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  • Katsunori NAKAMURA, Naoki MATSUZAWA, Shigeru OHMORI, Yuichi ANDO, Hiro ...
    2013 Volume 28 Issue 1 Pages 38-43
    Published: 2013
    Released: February 25, 2013
    [Advance publication] Released: November 20, 2012
    JOURNALS FREE ACCESS
      The teratogenic effects of thalidomide have been studied for more than 50 years. However, there have been few studies of the pharmacokinetic changes occurring during thalidomide therapy. Thalidomide was originally developed as a sedative. However, thalidomide induces multiple birth defects when used in pregnant women. Thalidomide is now used in the treatment of multiple myeloma (MM) and erythema nodosum leprosum (ENL) in Japan. Rational use of thalidomide is problematic due to a lack of basic research regarding its mechanism of action and serum concentration/effect relationships. There are a number of hypotheses for pharmacokinetic changes in thalidomide therapy. Genetic factors including single nucleotide polymorphisms (SNPs) that change cytochrome P450 (CYP) activity and epigenetic regulation that modifies CYP expression levels may contribute to the changes in pharmacokinetics and adverse drug reactions (ADRs) of thalidomide. Environmental factors include the pharmacological context of drug-drug interactions and the physiological context of liver diseases. Liver and kidney diseases do not play important roles in pharmacokinetic changes or ADRs in thalidomide therapy. To date, most research has focused on teratogenic activity, while the impact of polymorphisms in genes encoding drug metabolic enzymes and drug-drug interactions could mediate ADRs. Here, we discuss clinical evidence of pharmacokinetic changes in thalidomide therapy.
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Original Articles
Regular Articles
  • Keiichiro HIGASHI, Chihiro TANAKA, Kaori IMANISHI, Kazuki SAWAMOTO, Ta ...
    2013 Volume 28 Issue 1 Pages 44-52
    Published: 2013
    Released: February 25, 2013
    [Advance publication] Released: July 10, 2012
    JOURNALS FREE ACCESS
      This study was designed to clarify the influence of long-term enteral nutrition (EN) on the pharmacokinetics of digoxin. Rats were fed EN diets (semi-digested, digested, and elemental) for 4 weeks, then digoxin (0.05 mg/kg) was administered orally. The AUC0–∞ and ka of digoxin were significantly reduced in the semi-digested diet group versus the control, while the AUC0–∞ was significantly increased in the digested and elemental diet groups. The mRNA level of Slco1a4 was significantly reduced at the upper small intestine in all EN groups. Further, the expression levels of P-glycoprotein (P-gp) protein and Abcb1a mRNA were increased at the same site in all EN groups, and the increases were significant in the elemental diet group. Cyp3a2 protein and mRNA expressions were significantly reduced in the liver in the digested and elemental diet groups. Abcb1a mRNA was also significantly reduced in the kidney in these groups. These results indicate that the absorption kinetics at the small intestine is influenced by semi-digested diet, and the elimination kinetics in the liver and kidney are influenced by digested and elemental diet. Semi-digested diet also altered digoxin pharmacokinetics in humans. Thus, the effect of long-term EN on digoxin pharmacokinetics depended on the dietary components.
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  • Chia-Hsien CHANG, Yea-Huei Kao YANG, Swu-Jane LIN, Jyun-Jhong SU, Chin ...
    2013 Volume 28 Issue 1 Pages 53-58
    Published: 2013
    Released: February 25, 2013
    [Advance publication] Released: July 17, 2012
    JOURNALS FREE ACCESS
      Use of β-blockers may cause insomnia and central nervous system and/or psychological side effects, but data are limited on the relative risks of insomnia among β-blockers. This retrospective cohort study used Taiwan's National Health Insurance claims database from 2003 to 2007, where 4,063 patients aged above 65 years with newly diagnosed hypertension and treated with β-blockers were followed for 1 year. The primary endpoint was a new insomnia event within 30 days of treatment initiation. Adjusted odds ratios of insomnia were obtained by logistic regressions, controlling for baseline risk factors of insomnia. Using propranolol therapy as the reference, the adjusted odds ratio (95% confidence interval) for the insomnia risk was 0.47 (0.35–0.63) for non-propranolol users, 0.31 (0.19–0.50) for bisoprolol, and 0.46 (0.33–0.66) for atenolol. Compared to the patients using non-selective β-blockers, the adjusted odds ratio was 0.48 (0.36–0.34) for those using selective β1-blockers. Additionally, the adjusted odds ratio was 0.72 (0.53–0.96) for β-blockers with low lipophilicity when compared to those with high lipophilicity. The use of bisoprolol and atenolol was associated with the lowest risk of insomnia in elderly patients, as compared to propranolol. β-Blockers with high selectivity in β1-receptors and/or low lipophilicity were associated with a lower risk of insomnia.
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  • Takahiko TANIGAWA, Masato KANEKO, Kensei HASHIZUME, Mariko KAJIKAWA, H ...
    2013 Volume 28 Issue 1 Pages 59-70
    Published: 2013
    Released: February 25, 2013
    [Advance publication] Released: July 17, 2012
    JOURNALS FREE ACCESS
      The global ROCKET AF phase III trial evaluated rivaroxaban 20 mg once daily (o.d.) for stroke prevention in atrial fibrillation (AF). Based on rivaroxaban pharmacokinetics in Japanese subjects and lower anticoagulation preferences in Japan, particularly in elderly patients, the optimal dose regimen for Japanese AF patients was considered. The aim of this analysis was dose selection for Japanese patients from a pharmacokinetic aspect by comparison of simulated exposure in Japanese patients with those in Caucasian patients. As a result of population pharmacokinetics-pharmacodynamics analyses, a one-compartment pharmacokinetic model with first-order absorption and direct link pharmacokinetic-pharmacodynamic models optimally described the plasma concentration and pharmacodynamic models (Factor Xa activity, prothrombin time, activated partial thromboplastin time, and HepTest), which were also consistent with previous works. Steady-state simulations indicated 15 mg rivaroxaban o.d. doses in Japanese patients with AF would yield exposures comparable to the 20 mg o.d. dose in Caucasian patients with AF. In conclusion, in the context of the lower anticoagulation targets in Japanese practice, the population pharmacokinetic and pharmacodynamic modeling supports 15 mg o.d. as the principal rivaroxaban dose in J-ROCKET AF.
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Notes
  • Atsuko TOMARU, Nozomi MORIMOTO, Mariko MORISHITA, Kozo TAKAYAMA, Takuy ...
    2013 Volume 28 Issue 1 Pages 71-74
    Published: 2013
    Released: February 25, 2013
    [Advance publication] Released: July 03, 2012
    JOURNALS FREE ACCESS
      Oral sulfasalazine (SASP) is now used clinically as a probe substrate of a breast cancer resistance protein (BCRP) activity; however the intestinal absorption characteristics of SASP are not well understood. The purpose of this study was to clarify the characteristics of SASP transport in the mouse intestine. The everted ileum was incubated with SASP in the absence or presence of the Bcrp inhibitor Ko134. The steady-state intestinal absorptive clearance was 0.14 µL/min/cm in the absence of Ko134 and increased by 4.8-fold in the presence of Ko134. These results indicate that Bcrp mediates the efflux of SASP in the intestine. The absorptive clearance of SASP did not change in a concentration-dependent manner in the range of 0.1 to 50 µM in wild-type mice. By contrast, the absorptive clearance of SASP decreased significantly in a concentration-dependent manner in the presence of Ko134. Similar results were obtained in Bcrp−/− mice. These results suggest the possible involvement of some influx transporters in the intestinal absorption of SASP. In conclusion, both the influx and efflux transporters are involved in the intestinal absorption of SASP, which would explain why the absorptive clearance did not appear to change at various SASP concentrations in wild-type mice.
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  • Kazuya ISHIDA, Miki FUKAO, Hitomi WATANABE, Masato TAGUCHI, Toshio MIY ...
    2013 Volume 28 Issue 1 Pages 75-80
    Published: 2013
    Released: February 25, 2013
    [Advance publication] Released: July 17, 2012
    JOURNALS FREE ACCESS
      Bioavailability of mizoribine in subjects with the concentrative nucleoside transporter 1 (CNT1, SLC28A1) 565-A/A allele is significantly lower than that in subjects with the SLC28A1 565-G/G allele. The aims of the present study were to investigate the cellular uptake of mizoribine in CNT1- and CNT2-expressing Madin-Darby canine kidney type II (MDCKII) cells, and to evaluate the effect of salt intake on bioavailability of mizoribine in healthy Japanese volunteers with SLC28A1 565-A/A and -G/A alleles. Eight healthy males participated in the present study, and took 150 mg mizoribine concomitantly with/without 300 mg salt. Bioavailability of mizoribine was estimated by total cumulative urinary excretion of the drug. Mizoribine was taken up Na+-dependently into not only CNT1-expressing but also CNT2-expressing MDCKII cells, indicating that mizoribine is a substrate for both CNT1 and CNT2. Mean bioavailability of mizoribine taken with salt (83.8%) was significantly higher than that taken without salt (73.0%). These findings suggest that the salt intake is expected to improve the bioavailability of mizoribine in patients with insufficient intestinal absorption.
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