Reduced folate derivatives are endogenous substrates for cMOAT in rats

Kusuhara, Hiroyuki; Han, Yong‐Hae; Shimoda, Minoru; Kokue, Eiichi; Suzuki, Hiroshi; Sugiyama, Yuichi

doi:10.1152/ajpgi.1998.275.4.g789

Cited by 17 publications

(17 citation statements)

References 37 publications

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“…Similar transporters to this OATP-2 were confirmed in the rat liver, OATP-1/4 (3,17). It has been reported that endogenous reduced folate [8], PV [9,18] and methotrexate [11] are the substrate of these transporters. Supposing that rabbits might also have a similar transporter in their liver, we examined the pharmacokinetics of FNX in rabbits using concomitant administration of a large amount of PV, expecting to block possible FNX uptake into the liver cells by means of PV.…”

Section: Discussionsupporting

confidence: 69%

Possible Active Transport Mechanism in Pharmacokinetics of Flunixin-Meglumin in Rabbits.

et al. 2001

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ABSTRACT. The plasma and urine kinetics of flunixin-meglumin (FNX, 2 mg/kg, i.v.) in rabbits were examined. Unusual pharmacokinetic profiles were obtained, including high binding percentage with plasma protein (> 99%), a short elimination half-life (< 4 hr) and a relatively large Vd-area (0.5 L/kg). These profiles indicate that some active transport mechanisms are involved in FNX disposition. The recovery of FNX from urine was approximately 9 % of the dose within 24 hr following the injection. The estimated renal clearance of the unbound drug nearly corresponded to the renal blood flow rates, indicating that active tubular secretion in the renal re-absorptive tract may be involved in the disposition. The effect of a concomitant administration of pravastatin (PV) on FNX disposition was also examined. PV is a representative substrate of a transporter in human liver cells (OATP-2). After the PV administrations, the Vd-area of FNX and total body clearance markedly decreased, indicating that FNX is actively taken up and metabolized in liver cells by an OATP-2 like transporter. In conclusion, there are at least 2 active transport pathways for FNX pharmacokinetics in rabbits, one is renal tubular secretion and the other is in the sinusoidal section of the liver.

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Section: Discussionsupporting

confidence: 69%

Possible Active Transport Mechanism in Pharmacokinetics of Flunixin-Meglumin in Rabbits.

et al. 2001

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“…ATP-dependent MTX transport was also shown to be absent in canalicular membranes prepared from the liver of these animals (Masuda et al, 1997). Subsequent studies established that THF, 5-CH 3 -THF, 5-10-CH 2 -THF, and 10-CHO-THF are also substrates for MRP2 (Kusuhara et al, 1998).…”

Section: Mrps and Their Role In Antifolate Resistancementioning

confidence: 99%

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2003

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“…Transport across the bile canalicular membrane of many organic anions including glutathione, glucuronide and sulfate conjugates is mediated by an active transporter, a so-called canalicular multispecific organic anion transporter (cMOAT) [3]. Recently, it has been shown that the substrates for cMOAT also include MTX [4] and reduced folate derivatives [5]. There is increasing evidence in the literature of an inducing effect of a variety of cytotoxic, carcinogenic, and chemotherapeutic agents on cMOAT [6].…”

Section: Introductionmentioning

confidence: 99%

No Effect of Phenobarbital Pretreatment of Rats on Methotrexate Pharmacokinetics in the Isolated Liver Perfused in a Single-Pass Way

Chládek

Martı́nková²,

Šišpera³

et al. 2001

Pharmacology

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Pretreatment of the rat with phenobarbital (PB) is known to increase gene expression of the canalicular multispecific organic anion transporter (cMOAT) and hepatobiliary transport of its substrates (glutathione, sulfobromophthalein). To determine the effect of PB on the hepatobiliary transport of methotrexate (MTX, another substrate of cMOAT) and its metabolism to 7-hydroxymethotrexate (7-OHMTX) in the rat, we compared the steady-state pharmacokinetics of MTX in the isolated liver of either PB-pretreated (80 mg/day/kg bw for 4 days, i.p.) or nonpretreated rats. The livers were perfused in a single-pass way at a flow rate of 15 ml/min using a perfusate which consisted of Krebs-Henseleit buffer containing glucose, taurocholate, bovine albumin and erythrocytes. During the perfusion with 50 µmol/l MTX, the steady-state biliary clearance (1.26 ± 0.24 ml/min) in 7 nonpretreated rats accounted for a major proportion of the hepatic clearance (1.30 ± 0.33 ml/min), metabolism of MTX to 7- OHMTX was minor (partial metabolic clearance = 0.041 ± 0.023 ml/min). MTX concentrations in bile surpassed those in the input perfusate by approximately 100-fold. Pretreatment of rats (n = 7) with PB did not change significantly the steady-state hepatic, biliary and partial metabolic clearances of 50 µmol/l MTX. An interesting result is a 38% increase in the hepatic vascular resistance of non-pretreated livers caused by MTX. The results suggest that in rats, pretreatment with PB has no effect on the hepatobiliary transport and hydroxylation of MTX.

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Reduced folate derivatives are endogenous substrates for cMOAT in rats

Cited by 17 publications

References 37 publications

Possible Active Transport Mechanism in Pharmacokinetics of Flunixin-Meglumin in Rabbits.

Possible Active Transport Mechanism in Pharmacokinetics of Flunixin-Meglumin in Rabbits.

Resistance to antifolates

No Effect of Phenobarbital Pretreatment of Rats on Methotrexate Pharmacokinetics in the Isolated Liver Perfused in a Single-Pass Way

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