Effects of dose, flow rate, and bile acid on diclofenac disposition in the perfused rat liver

Uraki, Misato; Kawase, Atsushi; Matsushima, Yuta; Iwaki, Masahiro

doi:10.1007/s13318-015-0259-4

Cited by 7 publications

(3 citation statements)

References 25 publications

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“…In situ liver perfusion was performed similarly as the method described previously (Uraki et al, 2016 ). Rats were cannulated in the bile duct, hepatic portal vein, and inferior vena cava.…”

Section: Methodsmentioning

confidence: 99%

The Cytochrome P450-Mediated Metabolism Alternation of Four Effective Lignans From Schisandra chinensis in Carbon Tetrachloride-Intoxicated Rats and Patients With Advanced Hepatocellular Carcinoma

Xiao²,

Zhang³

et al. 2018

Front. Pharmacol.

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It is highly valuable to study the pharmacokinetics of herbal components under the pathological condition of liver dysfunction for safe and rational use of herbal medicines. In this study, the pharmacokinetic profiles of four effective lignans from Schisandra chinensis (SC), schisandrin, schisantherin A, deoxyshisandrin and γ-schisandrin, were investigated in carbon tetrachloride (CCl4)-intoxicated rats. The metabolism of the four lignans was also studied using microsomes from patients with advanced hepatocellular carcinoma. In situ intestinal and hepatic perfusions were conducted to clarify the contributions from impairments of gut and liver on the pharmacokinetics of the four schisandra lignans in CCl4-intoxicated rats. The metabolism in rat and human liver microsomes and transport in Caco-2 monolayer cell model were studied to reveal the key factors for the in vivo disposition of the four lignans. When SC alcoholic extract was orally administrated to CCl4-intoxicated rat for a short term (4 days), the pharmacokinetics of four active SC lignans was significantly changed while its hepatotherapeutic effect was not obviously observed. The plasma concentrations of the four schisandra lignans were dramatically elevated compared with the control. The Cmax, AUC and MRT were all increased or prolonged significantly while parameter CLz/F was obviously reduced in rat pretreated with CCl4. In hepatic perfusion study and liver microsomes incubation, it was found that the hepatic metabolism of the four lignans was markedly decreased mainly due to the activity reduction of multiple CYP450 isoenzymes involved the metabolism, which, eventually, might lead to the alternation of their pharmacokinetic profiles in CCl4-intoxicated rats or patients with advanced hepatocellular carcinoma. The pharmacokinetic studies of SC components in pathological situation of liver dysfunction are expected to provide useful data for rational and safe application of SC preparations in clinic or further pharmacological and toxicological research.

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Section: Methodsmentioning

confidence: 99%

The Cytochrome P450-Mediated Metabolism Alternation of Four Effective Lignans From Schisandra chinensis in Carbon Tetrachloride-Intoxicated Rats and Patients With Advanced Hepatocellular Carcinoma

Xiao²,

Zhang³

et al. 2018

Front. Pharmacol.

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“…19) The generated NSAIDs-Glu molecules are secreted into the blood along with bile. 20) Separately, NSAIDs taken into tubular cells are also converted into glucuronide conjugates mainly by uridine diphosphate (UDP)-glucuronosyl transferase (UGT) 2B7. 21,22) Most NSAIDs-Glu molecules are excreted directly into urine.…”

mentioning

confidence: 99%

Inhibition of Methotrexate Uptake via Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs

Iwaki

Shimada

Irino

et al. 2017

Biological & Pharmaceutical Bulletin

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Combination therapy of non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate (MTX) sometimes triggers adverse effects, such as liver injury, renal failure, gastrointestinal disorders, and myelosuppression, owing to the reduction of MTX clearance. Previous reports have suggested that NSAIDs inhibit renal MTX uptake via organic anion transporters (OATs) and reduced folate transporter (RFC)-1 and efflux via multidrug resistance-associated proteins (MRPs). Recently, our laboratory found inhibitory effects of NSAIDs-glucuronide (NSAIDs-Glu), a major metabolite of NSAIDs, on MRP-mediated MTX transport as a new site of interaction between MTX and NSAIDs. However, it remains unclear that whether NSAIDsGlu inhibit renal uptake of MTX. Therefore, the present study aimed to evaluate inhibitory effects of several NSAIDs-Glu (diclofenac, R-and S-ibuprofen, R-and S-flurbiprofen, and R-and S-naproxen) on human OAT1 and OAT3-mediated MTX transport. In this study, [ 3 H]MTX uptake was observed by using human OAT1 and OAT3-overexpressing HEK293 cells in the presence or absence of NSAIDs-Glu. All examined NSAIDs-Glu exhibited concentration-dependent inhibitory effects on MTX uptake via OAT1 and OAT3. Our results indicated that NSAIDs-Glu are more potent (5-to 15-fold) inhibitors of OAT3 than OAT1. Moreover, stereoselective inhibitory effects of NSAIDs-Glu on OATs-mediated MTX uptake were not observed, unlike on MRPs-mediated transport. These findings suggest that inhibition of OAT1 and OAT3-mediated renal uptake of MTX by plasma NSAIDs-Glu may be one of the competitive sites underlying complex drug interaction between MTX and NSAIDs.Key words drug interaction; methotrexate; non-steroidal anti-inflammatory drug; glucuronide; organic anion transporter Although methotrexate (MTX) is often co-administered with non-steroidal anti-inflammatory drugs (NSAIDs) to patients suffering from rheumatoid arthritis and neoplastic diseases, several NSAIDs, such as ketoprofen, indomethacin, naproxen, and diclofenac, reduce MTX clearance. Thus, combined administration of MTX and NSAIDs can result in elevated plasma MTX concentrations and severe adverse effects, such as liver injury, renal failure, gastrointestinal disorders, and myelosuppression. [1][2][3][4][5] In fact, the MTX prescribers' information states that combined use of MTX and NSAIDs may increase plasma MTX concentrations and adverse effects.MTX is primarily excreted in urine via glomerular filtration and active tubular secretion in its unchanged form.6) At a clinical plasma concentration of MTX (0.2-10 µM), approximately 25% of renal clearance is excreted by glomerular filtration and the remaining 75% is excreted by active tubular secretion. 7)In the tubular secretory process, organic anion transporters (OAT) 1 and 3 and reduced folate carrier (RFC)-1 transport MTX from the blood across the basolateral membrane. [8][9][10][11] Multidrug resistance-related proteins (MRP) 2 and 4 and breast cancer-resistant protein (BCRP) transport MTX across the apical membrane into the urine w...

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“…In situ rat liver perfusion was performed by the procedure described in previous report [22]. Briefly, the perfusion medium volume was 100 ml consisted of Krebs-Ringer-bicarbonate solution with 24 µmol/l taurocholic acid.…”

Section: In Situ Rat Liver Perfusionmentioning

confidence: 99%

Effects of Fasting on Pravastatin Disposition in Perfused Rat Liver

Kawase

Handa

Iwaki

2016

Int J Pharm Pharm Sci

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Objective: Various nutrients such as glucose and cholesterol affect the expression of hepatic transporters. Although the pharmacokinetics of some drugs is affected by fasting, the fasting effects on drug hepatic disposition via alterations in transporters are unclear. Organic anion-transporting polypeptides and multidrug resistance-associated protein 2 (Mrp2/Abcc2) expressed in the liver are involved in hepatic disposition of pravastatin.Methods: An in situ perfused rat liver system was established. The mRNA and protein levels of transporters in the liver were examined by real-time reverse transcription PCR and western blotting. The localization of Mrp2 in hepatocytes was determined by immunostaining.Results: Pravastatin was rapidly eliminated from the perfusate. The cumulative biliary excretion amounts of pravastatin in fasting rats were significantly lower from 10 min compared with control. In fasting rats, the area under the plasma concentration-time curve (AUC)0‒∞ of pravastatin in the perfusate was significantly decreased, and hepatic clearance (CLh) and hepatic corrected clearance (CLcor) were significantly increased. The biliary clearance (CLbile) in fasting rats tended to decrease compared with that in control rats. Protein expression levels of transporters were unchanged after fasting. Confocal microscopy revealed a disruption of Mrp2 and ZO-1 colocalization in the liver of fasting rats.Conclusion: The biliary excretion of pravastatin was inhibited by fasting via decreased Mrp2 localization on the canalicular membrane.

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Effects of dose, flow rate, and bile acid on diclofenac disposition in the perfused rat liver

Cited by 7 publications

References 25 publications

The Cytochrome P450-Mediated Metabolism Alternation of Four Effective Lignans From Schisandra chinensis in Carbon Tetrachloride-Intoxicated Rats and Patients With Advanced Hepatocellular Carcinoma

The Cytochrome P450-Mediated Metabolism Alternation of Four Effective Lignans From Schisandra chinensis in Carbon Tetrachloride-Intoxicated Rats and Patients With Advanced Hepatocellular Carcinoma

Inhibition of Methotrexate Uptake <i>via</i> Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs

Effects of Fasting on Pravastatin Disposition in Perfused Rat Liver

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