Role of Mrp2 in the Hepatic Disposition of Mycophenolic Acid and Its Glucuronide Metabolites: Effect of Cyclosporine

Westley, Ian S.; Brogan, Leonie R.; Morris, Raymond G.; Evans, Allan M.; Sallustio, Benedetta C.

doi:10.1124/dmd.105.006122

Cited by 97 publications

(79 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our rat studies, the acyl glucuronide also represented a minor metabolite, accounting for less then approximately 5% of total glucuronides (data not shown), in agreement with formation rates in perfused rat liver (Westley et al, 2006). Some researchers, however, have proposed that even though the acyl glucuronide is a minor metabolite, it could play a role in MMF GI side effects and therapeutic efficacy (Shipkova et al, 2002).…”

Section: Discussionsupporting

confidence: 59%

“…6) may result from elevated transport or enhanced generation of MPAG in the male rats. Although evidence that MPAG is excreted into the bile by MRP2 (Kobayashi et al, 2004) was recently confirmed using TRϪ rats (Westley et al, 2006), studies have not observed differences in hepatic MRP2 mRNA levels between male and female rats at 3 months of age and older (Johnson et al, 2002). Thus, it would seem that the increased excretion of MPAG into the bile of male rats is the direct result of increased formation of the metabolite rather than increased transport in the male rats.…”

Section: Discussionmentioning

confidence: 88%

See 1 more Smart Citation

Gender-Related Differences in Mycophenolate Mofetil-Induced Gastrointestinal Toxicity in Rats

Stern¹,

Tallman²,

Miles³

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is included in current combination immunosuppressive regimens following organ transplant. Treatment with MMF often results in dose-limiting gastrointestinal (GI) side effects. The underlying mechanisms responsible for these side effects are not fully understood, but exposure of the intestinal epithelia to MPA during enterohepatic recycling may be involved. The present study demonstrated that female rats are more susceptible to MMF-induced GI toxicity than male rats. Female Sprague-Dawley rats treated chronically with an oral dose of 50 mg of MPA equivalents/kg/day experienced greater GI toxicity than male rats, as measured by diarrhea grade and weight loss. Intestinal microsomes harvested from the upper jejunum of female rats had approximately 3-fold lower MPA glucuronidation rates compared with male rats. In the remaining areas of the small and large intestine, there was also a trend toward decreased glucuronidation in the female rats. The area under the plasma concentration-time curve (AUC) for MPA following an oral dose of 50 mg of MPA equivalents/kg was roughly similar between genders, whereas the AUC for mycophenolic acid phenolic glucuronide (MPAG) was significantly lower in female rats. Female rats also excreted half of the biliary MPAG as male rats. The greater susceptibility of female rats to MMF-induced gastrointestinal toxicity, despite diminished intestinal MPA exposure via reduced biliary excretion of MPAG, may result from reduced protection of enterocytes by in situ glucuronidation. Likewise, susceptibility to MMF-induced GI toxicity in humans may also result from variable intestinal glucuronidation due to UDP glucuronosyltransferase polymorphisms or differential expression.

show abstract

Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 88%

Gender-Related Differences in Mycophenolate Mofetil-Induced Gastrointestinal Toxicity in Rats

Stern¹,

Tallman²,

Miles³

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Mrp2, a transport protein localized on the hepatic canalicular plasma membrane, is responsible for the biliary excretion of organic anions as well as numerous drugs including pravastatin, vincristine and etoposide Kawabe et al, 1999;Konig et al, 1999;Sasaki et al, 2002). Animals with hereditary conjugated hyperbilirubinemia [Mrp2-deficient rats (TR − ) and Eisai hyperbilirubinemic rats (EHBR)] have been used extensively to examine the substrate specificity and in vivo function of Mrp2 (Westley et al, 2006;ZamekGliszczynski et al, 2006). Patients with Dubin-Johnson syndrome lack MRP2 and hence suffer from hereditary conjugated hyperbilirubinemia (Paulusma et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance-associated proteins (Mrps) may prevent hepatotoxicity

Lee

Leslie

Zamek‐Gliszczynski

et al. 2008

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Trabectedin is a promising anticancer agent, but dose-limiting hepatotoxicity was observed during phase I/II clinical trials. Dexamethasone (DEX) has been shown to significantly reduce trabectedinmediated hepatotoxicity. The current study was designed to assess the capability of sandwichcultured primary rat hepatocytes (SCRH) to predict the hepato-protective effect of DEX against trabectedin-mediated cytotoxicity. The role of multidrug resistance-associated protein 2 (Mrp2; Abcc2) in trabectedin hepatic disposition also was examined. In SCRH from wild-type Wistar rats, cytotoxicity was observed after 24-hr continuous exposure to trabectedin. SCRH pretreated with additional DEX (1 µM) exhibited a 2-3-fold decrease in toxicity at 100 nM and 1000 nM trabectedin. Unexpectedly, toxicity in SCRH from Mrp2-deficient (TR − ) compared to wild-type Wistar rats was markedly reduced. Depletion of glutathione from SCRH using buthionine sulfoximine (BSO) mitigated trabectedin toxicity associated with 100 nM and 1000 nM trabectedin. Western blot analysis demonstrated increased levels of CYP3A1/2 and Mrp2 in SCRH pretreated with DEX; interestingly, Mrp4 expression was increased in SCRH after BSO exposure. Trabectedin biliary recovery in isolated perfused livers from TR − rats was decreased by ~75% compared to wild-type livers. In conclusion, SCRH represent a useful in vitro model to predict the hepatotoxicity of trabectedin observed in vivo. The protection by DEX against trabectedin-mediated cytotoxicity may be attributed, in part, to enhanced Mrp2 biliary excretion and increased metabolism by CYP3A1/2. Decreased trabectedin toxicity in SCRH from TR − rats, and in SCRH pretreated with BSO, may be due to increased basolateral excretion of trabectedin by Mrp3 and/or Mrp4.

show abstract

“…Using TR Ϫ rats, a strain of mutant Wistar rats lacking the Mrp2 transporter (Soroka et al, 2001) Mrp2 has been shown to be the key transporter involved in MPAGe biliary excretion in rats (Kobayashi et al, 2004;Hesselink et al, 2005;Westley et al, 2006). We have previously reported that in perfused TR Ϫ rat livers, the clearance (CL) and hepatic extraction ratio of MPA were significantly lower compared with control Wistar rats (Westley et al, 2006). One possible mecha-nism for this observation is that there was a difference in the capacity of the TR Ϫ rats to metabolize MPA compared with the control Wistar rats in situ.…”

mentioning

confidence: 99%

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR^- Rat Liver Microsomes

Westley

Morris²,

Evans³

et al. 2007

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

show abstract

Role of Mrp2 in the Hepatic Disposition of Mycophenolic Acid and Its Glucuronide Metabolites: Effect of Cyclosporine

Cited by 97 publications

References 34 publications

Gender-Related Differences in Mycophenolate Mofetil-Induced Gastrointestinal Toxicity in Rats

Gender-Related Differences in Mycophenolate Mofetil-Induced Gastrointestinal Toxicity in Rats

Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance-associated proteins (Mrps) may prevent hepatotoxicity

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR^- Rat Liver Microsomes

Contact Info

Product

Resources

About

Role of Mrp2 in the Hepatic Disposition of Mycophenolic Acid and Its Glucuronide Metabolites: Effect of Cyclosporine

Cited by 97 publications

References 34 publications

Gender-Related Differences in Mycophenolate Mofetil-Induced Gastrointestinal Toxicity in Rats

Gender-Related Differences in Mycophenolate Mofetil-Induced Gastrointestinal Toxicity in Rats

Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance-associated proteins (Mrps) may prevent hepatotoxicity

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR- Rat Liver Microsomes

Contact Info

Product

Resources

About

Glucuronidation of Mycophenolic Acid by Wistar and Mrp2-Deficient TR^- Rat Liver Microsomes