Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics

Khamdang, Suparat; Takeda, Michio; Babu, Ellappan; Noshiro, Rie; Onozato, Maristela L.; Tojo, Akihiro; Enomoto, Atsushi; Huang, Xiu-Lin; Narikawa, Shinichi; Anzai, Naohiko; Piyachaturawat, Pawinee; Endou, Hitoshi

doi:10.1016/s0014-2999(03)01381-5

Cited by 82 publications

(42 citation statements)

References 24 publications

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“…5D) of that of the control group. To further examine the mechanism for renal excretion of JBP485 and cephalexin, the drugs were administered intravenously with 200 mg/kg probenecid (a classic substrate of OATs) (Khamdang et al, 2003). Probenecid inhibited further the renal excretion of JBP485 and cephalexin when the three drugs were administered together (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Interaction between JBP485 and Cephalexin in Rats

Zhang¹,

Wang²,

Liu³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The purpose of this study was to investigate the pharmacokinetic mechanism of interaction between JBP485 (cyclo-trans-4-L-hydroxyprolyl-L-serine, a dipeptide) and cephalexin when they were coadministered in rats. The plasma concentrations of JBP485 and cephalexin were both decreased significantly after oral combination, but little difference was observed after simultaneous intravenous administration of the two agents, suggesting that the interaction target localized in the intestine during the absorption process. The uptake in everted intestinal sacs and absorption in jejunal perfusions of JBP485 and cephalexin were dramatically reduced after drug combination. When JBP485 and cephalexin were coadministered, both the decrease in accumulative renal excretion (81.9-68.1% of JBP485 and 91.8-74.5% of cephalexin) and in renal clearance (2.89-1.87 ml/min/kg JBP485 and 2.23-1.58 ml/min/kg cephalexin) indicated that transporter(s) other than H ؉ / peptide transporter (PEPT) 2 are involved in the process of excretion. Probenecid could reduce renal excretion of JBP485 and cephalexin. Moreover, the decreased uptake of JBP485 with probenecid, p-aminohippuate, or benzylpenicillin in kidney slices could be explained by an inhibition in the kidney via organic anion transporters (OATs), at least in part. The accumulation of JBP485 in human (h) OAT1-or hOAT3-human embryonic kidney (HEK) 293 cells was greater than that in vector-HEK293 cells, and the uptake could be inhibited by probenecid. These findings further confirmed that the pharmacokinetic mechanism of the drug-drug interaction between JBP485 and cephalexin could be explained by their inhibition of the same transporters in the intestinal mucosa (PEPT1) and kidneys (PEPT2 and OATs). We provide the first evidence that JBP485 is not only a substrate of PEPTs but also is excreted through OATs.

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Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Interaction between JBP485 and Cephalexin in Rats

Zhang¹,

Wang²,

Liu³

et al. 2010

Drug Metab Dispos

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“…The hOAT4 is unique member among organic anion transporter family expressed in the placenta. Recently isolated hOAT4 is thought to play important role as a steroid sulfate conjugate transporter and also contributes elimination of clinically important drugs and endogenous organic anions (Khamdang et al, 2003;Ugele et al, 2003;Ekaratanawong et al, 2004). Even though the regulation mechanism of hOAT4 in the kidney has begun to be explored, its regulation mechanism in the placenta is largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Co-localization and interaction of human organic anion transporter 4 with caveolin-1 in primary cultured human placental trophoblasts

Lee¹,

Choi

2008

Exp Mol Med

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The human organic anion transporter 4 (hOAT4) has been identified as the fourth isoform of OAT family. hOAT4 contributes to move several negatively charged organic compounds between cells and their extracellular milieu. The functional characteristics and regulatory mechanisms of hOAT4 remain to be elucidated. It is well known that caveolin plays a role in modulating proteins having some biological functions. To address this issue, we investigated the co-localization and interaction between hOAT4 and caveolin-1. hOAT4 and caveolin-1 (mRNA and protein expression) were observed in cultured human placental trophoblasts isolated from placenta. The confocal microscopy of immuno-cytochemistry using primary cultured human trophoblasts showed hOAT4 and caveolin-1 were co-localized at the plasma membrane of the cell. This finding was confirmed by Western blot analysis using isolated caveolae-enriched membrane fractions and immune-precipitates from the trophoblasts. When synthesized cRNA of hOAT4 along with scrambled-or antisense-oligodeoxynucleotide (ODN) of Xenopus caveolin-1 were co-injected to Xenopus oocytes, the [ 3 H]estrone sulfate uptake was significantly decreased by the co-injection of antisense ODN but not by scrambled ODN. These findings suggest that hOAT4 and caveolin-1 share a cellular expression in the plasma membrane and caveolin-1 up-regulates the organic anionic compound uptake by hOAT4 under the normal physiological condition.

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“…Organic anion transporters such as OAT2 (SLC22A7) and OATPs (SLC21A) expressed on the sinusoidal membrane of the liver are thought to be responsible for the uptake of ß-lactam antibiotics from blood into hepatocytes. 38 Khamdang et al 39 demonstrated that hOAT2 and intravenous administration of ampicillin at the dose of 180 μmol/kg to rats induced choleresis, but this was not observed in rMRP2-deficient TR -. 42 Ito et al 43 demonstrated that ß-lactam antibiotics which are rMRP2 substrates induce choleresis via the stimulation of rMRP2-mediated GSH excretion into bile.…”

Section: ) Elimination From the Livermentioning

confidence: 99%

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

Tsuji¹

2006

Journal of Infection and Chemotherapy

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Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics

Cited by 82 publications

References 24 publications

Pharmacokinetic Interaction between JBP485 and Cephalexin in Rats

Pharmacokinetic Interaction between JBP485 and Cephalexin in Rats

Co-localization and interaction of human organic anion transporter 4 with caveolin-1 in primary cultured human placental trophoblasts

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

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