Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
Volume 23 , Issue 4
Showing 1-10 articles out of 10 articles from the selected issue
Preface
Reviews
  • Kazuya MAEDA, Yuichi SUGIYAMA
    2008 Volume 23 Issue 4 Pages 223-235
    Published: 2008
    Released: September 02, 2008
    JOURNALS FREE ACCESS
      As the importance of drug transporters in the clinical pharmacokinetics of drugs is recognized, genetic polymorphisms of drug transporters have emerged as one of the determinant factors to produce the inter-individual variability of pharmacokinetics. Many clinical studies have shown the influence of genetic polymorphisms of drug transporters on the pharmacokinetics and subsequent pharmacological and toxicological effects of drugs. The functional change in a transporter in clearance organs such as liver and kidney affects the drug concentration in the blood circulation, while that in the pharmacological or toxicological target can alter the local concentration at the target sites without changing its plasma concentration. As for the transporters for organic anions, some single nucleotide polymorphisms (SNPs) or haplotypes occurring with high frequency in organic anion transporting polypeptide (OATP) 1B1, multidrug resistance 1 (MDR1), and breast cancer resistance protein (BCRP) have been extensively investigated in both human clinical studies and in vitro functional assays.
       We introduce some examples showing the relationship between haplotypes in transporters and pharmacokinetics and pharmacological effects of drugs. We also discuss how to predict the effect of functional changes in drug transporters caused by genetic polymorphisms on the pharmacokinetics of drugs from in vitro data.
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  • Mohamed A. KAMAL, Richard F. KEEP, David E. SMITH
    2008 Volume 23 Issue 4 Pages 236-242
    Published: 2008
    Released: September 02, 2008
    JOURNALS FREE ACCESS
      Pept2 knockout mice are an important tool to evaluate the evolving role and relevance of this proton-coupled oligopeptide transporter beyond drug disposition, where the transporter also modulates the pharmacodynamic and toxicodynamic effects of drug substrates. Our in vivo studies with glycylsarcosine in Pept2 knockout mice have established “proof of concept” that PEPT2 can have a significant effect on dipeptide disposition. Subsequent studies with the aminocephalosporin antibiotic cefadroxil have shown relevance to pharmacology and infectious disease. Finally, studies with the endogenous peptidomimetic 5-aminolevulinic acid have demonstrated relevance to toxicology in the framework of porphyria- and lead-induced neurotoxicity. These studies have consistently demonstrated the dual action of PEPT2 with respect to its apical localization in choroid plexus epithelium and kidney in: 1) effluxing substrates from CSF into choroid plexus, thereby affecting regional pharmacokinetics in brain; and 2) reabsorbing substrates from renal tubular fluid into proximal tubules, thereby affecting systemic pharmacokinetics and exposure. Moreover, these studies have shown that the regional effect of PEPT2 in limiting substrate concentrations in the CSF is more dramatic than its effect in increasing systemic exposure. In the case of 5-aminolevulinic acid, such regional modulation of drug disposition translates directly into significant changes in neurotoxicity.
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  • Min-Koo CHOI, Im-Sook SONG
    2008 Volume 23 Issue 4 Pages 243-253
    Published: 2008
    Released: September 02, 2008
    JOURNALS FREE ACCESS
      To clarify the considerable interindividual variability in the pharmacokinetics, efficacy, and toxicity of drugs, genetic polymorphism of drug transporters has attracted interest because these transporters play important roles in the gastrointestinal absorption, biliary and renal elimination, and distribution to target sites of their substrates. Of the over 325 members of the solute carrier superfamily, this review focuses on the molecular features, expressional regulation, and genetic polymorphisms of the organic cation transporter (OCT) family, and the pharmacokinetic or pharmacodynamic consequences for organic cationic drugs. Although the clinical significance is still unclear, many studies have reported the importance of OCTs in the tissue distribution and elimination of their substrates in vitro and in vivo, and the impact of functional non-synonymous single nucleotide polymorphisms or differential expression levels of OCTs on the large interindividual variation in the pharmacokinetics and response of organic cationic drugs such as metformin, imatinib, and cisplatin.
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Regular Articles
  • Santoshanand V. THAKKAR, Seiji MIYAUCHI, Puttur D. PRASAD, Vadivel GAN ...
    2008 Volume 23 Issue 4 Pages 254-262
    Published: 2008
    Released: September 02, 2008
    JOURNALS FREE ACCESS
      We have recently identified a Na+/Cl--coupled transport system in mammalian cells for endogenous and synthetic opioid peptides. This transport system does not transport dipeptides/tripeptides, but is stimulated by these small peptides. Here we investigated the influence of L-kyotorphin (L-Tyr-L-Arg), an endogenous dipeptide with opioid activity, on this transport system. The activity of the transport system, measured in SK-N-SH cells (a human neuronal cell line) with deltorphin II as a model substrate, was stimulated ~2.5-fold by L-kyotorphin, with half-maximal stimulation occurring at ~100 μM. The stimulation was associated primarily with an increase in the affinity for deltorphin II. The stimulation caused by L-kyotorphin was stereospecific; L-Tyr-D-Arg (D-kyotorphin) had minimal effect. The influence of L-kyotorphin was observed also in a different cell line which expressed the opioid peptide transport system. While L-kyotorphin is a stimulator of opioid peptide transport, it is a transportable substrate for the H+-coupled peptide transporter PEPT2, which is expressed widely in the brain. Since the activity of the opioid peptide transport system is modulated by extracellular L-kyotorphin and since PEPT2 is an important determinant of extracellular L-kyotorphin in the brain, the expression/activity of PEPT2 may be a critical factor in the modulation of opioidergic neurotransmission in vivo.
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  • Yan LI, Masanobu SATO, Yuichi YANAGISAWA, Hideaki MAMADA, Akimasa FUKU ...
    2008 Volume 23 Issue 4 Pages 263-270
    Published: 2008
    Released: September 02, 2008
    JOURNALS FREE ACCESS
      Elevated serum uric acid level has been associated with increased cardiovascular risk in hypertensive patients. Several angiotensin II receptor blockers exhibit differential effects on regulation of serum uric acid level in humans. We have demonstrated that some angiotensin II receptor blockers trans-stimulate the uptake of uric acid by human URAT1 and others inhibit the transport of uric acid mediated by human URAT1, OAT1, OAT3 and MRP4 in vitro. This study investigated the effects of candesartan, pratosartan and telmisartan on renal handling of uric acid in rats in vivo and in vitro. Candesartan (0.1 mg/kg) significantly decreased the urinary excretion of uric acid and increased the plasma uric acid concentration. The kidney candesartan level after low-dose treatment is close to that required to trans-stimulate uric acid uptake in vitro. Pratosartan exhibited dose-dependent hypouricemic and uricosuric effects, while telmisartan showed no effects on plasma uric acid level. Furthermore, we confirmed the effects of the tested drugs on uric acid transport by rat renal brush border membrane transporter(s) and basolateral Oat1 and Oat3. Effects of angiotensin II receptor blockers in rats may be mainly determined by their intrinsic effects (cis-inhibition and trans-stimulation) on uric acid reabsorption transporter(s) and their pharmacokinetic properties in rats.
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  • Kazuo NAKAMURA, Kimihiro ITO, Yukio KATO, Takeshi SUGAYA, Yoshiyuki KU ...
    2008 Volume 23 Issue 4 Pages 271-278
    Published: 2008
    Released: September 02, 2008
    JOURNALS FREE ACCESS
      A novel biomarker of renal dysfunction, liver-type fatty acid binding protein (L-FABP), which is expressed in human proximal tubules, binds to lipid peroxidation products during renal injury and is excreted into the urine. Here, we examined the usefulness of human L-FABP transgenic (Tg) mice as a tool to explore nephrotoxicity, employing two model drugs, cephaloridine and cisplatin, which are taken up by renal tubules via organic anion and cation transporters, respectively. Urinary excretion of L-FABP increased after administration of cephaloridine in most of the Tg mice, whereas glomerular filtration markers such as blood-urea-nitrogen (BUN) and plasma creatinine (CRE) were almost unchanged. Thus, L-FABP is a highly sensitive detector of the nephrotoxicity of cephaloridine. Urinary excretion of L-FABP in the Tg mice also increased after administration of cisplatin, and this increase was reduced by coadministration of cimetidine. Both BUN and CRE also increased after the cisplatin treatment, but these parameters were minimally affected by coadministration of cimetidine, suggesting that cimetidine reduces cisplatin-induced renal tubular toxicity with only a minimal effect on the glomerulus. These results indicate that the L-FABP Tg mouse should be a useful drug screening system to evaluate specifically the toxicity of transporter substrates to renal tubules.
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  • Yuriko OHGUSU, Kin-ya OHTA, Megumi ISHII, Takahiro KATANO, Kimihiko UR ...
    2008 Volume 23 Issue 4 Pages 279-284
    Published: 2008
    Released: September 02, 2008
    JOURNALS FREE ACCESS
      The mechanism of glycerol transport by human aquaporin 9 (hAQP9), which is a liver-specific AQP water channel and can also transport glycerol, was investigated by using the Xenopus laevis oocyte expression system. It was found that specific glycerol uptake by hAQP9 was concentration-dependent (saturable) at 25°C, conforming to the Michaelis-Menten kinetics with the maximum transport rate (Jmax) of 0.84 pmol/min/oocyte and the Michaelis constant (Km) of 9.2 μM, and temperature-dependent, being reduced by about 70% when temperature was lowered from 25°C to 4°C. Such dependences on concentration and temperature are characteristic of a carrier-mediated type of mechanism rather than a channel type, which is expected not to depend on them. Furthermore, several glycerol-related compounds, such as monoacetin, were found to specifically inhibit hAQP9-mediated glycerol uptake, indicating a possibility of competition with glycerol. hAQP9-mediated glycerol uptake was, however, found not to require Na+. All these results suggest that hAQP9 functions as a facilitative carrier for glycerol, although it had been believed to function as a channel. Findings in the present study provide novel insight into its glycerol-transporting mechanism and would help exploring a possibility that hAQP9 inhibitors might help lower blood glucose level by reducing gluconeogenesis by limiting hepatic glycerol uptake.
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  • Ken-ichi HOSOYA, Keiko FUJITA, Masanori TACHIKAWA
    2008 Volume 23 Issue 4 Pages 285-292
    Published: 2008
    Released: September 02, 2008
    JOURNALS FREE ACCESS
      The purpose of this study was to elucidate the mechanism of methyltetrahydrofolate (MTF) transport at the inner blood-retinal barrier (inner BRB). The characteristics and function of MTF transport at the inner BRB were examined using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2) as an in vitro model of the inner BRB. The [3H]MTF uptake by TR-iBRB2 cells increased with lowering extracellular pH and was Na+- and Cl--independent. The [3H]MTF uptake was concentration-dependent with a Km of 5.1 μM. This process was inhibited by reduced folate carrier 1 (RFC1) substrates, such as methotrexate and formyltetrahydrofolate, in a concentration-dependent manner with an IC50 of 8.7 and 2.8 μM, respectively, suggesting that RFC1 mediates MTF uptake in TR-iBRB2 cells. Although both RFC1 and proton-coupled folate transporter (PCFT) mRNA, which are pH-sensitive folate transporters, are expressed in TR-iBRB2 cells and isolated rat retinal vascular endothelial cells, the expression level of RFC1 mRNA was 83- and 49-fold greater than that of PCFT, respectively. Taken together, the above findings are consistent with the involvement of RFC1 in the inner BRB transport of MTF.
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  • Shuichi OHNISHI, Noboru OKAMURA, Shingo SAKAMOTO, Hiroshi HASEGAWA, Ry ...
    2008 Volume 23 Issue 4 Pages 293-303
    Published: 2008
    Released: September 02, 2008
    JOURNALS FREE ACCESS
      Pivalic acid and valproic acid decreases L-carnitine concentration in the body via urinary excretion of their acylcarnitines, pivaloylcarnitine (PC) and valproylcarnitine (VC). To obtain an information about the mechanism of the physiological response, we investigated the renal handling of these acylcarnitines by Na+/L-carnitine cotransporter, OCTN2 using the isolated perfused rat kidney, rat OCTN2 (rOCTN2) and human OCTN2 (hOCTN2) expressing cells. In the perfused rat kidney, PC and VC were strongly reabsorbed with an efficiency comparable to L-carnitine, and these reabsorption were inhibited by 1 mM L-carnitine, suggesting that the interaction of L-carnitine with PC and VC reabsorption would be responsible for renal handling of these acylcarnitines in rats. The rOCTN2-mediated uptake of PC was lower than that of L-carnitine, whereas rOCTN2-mediated uptake of VC was as high as that of L-carnitine, indicating that contribution of rOCTN2 in renal handling of PC and VC would be different. Furthermore, hOCTN2-mediated uptake of these acylcarnitines was markedly lower than that of L-carnitine. On the other hand, both PC and VC inhibited L-carnitine reabsorption in the perfused rat kidney and their concentration-dependent inhibition was also observed for rOCTN2 and hOCTN2. These results suggest that low renal reabsorption and interaction of hOCTN2 for these acylcarnitines might possibly affect the decrease of L-carnitine concentration in humans.
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