simultaneous determination of mycophenolic acid and its metabolites by HPLC and pharmacokinetic studies in rat plasma and bile

Gao, Junwei; Peng, Zhihai; Li, Xiaoyu; Sun, Bo; Guo, Ye; Gao-lin, Liu

doi:10.1007/s12272-011-0107-2

Cited by 17 publications

(22 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…20) In humans and rats, MMF is also known to exhibit EHC of MPA because its metabolite MPAG undergoes biliary excretion followed by deconjugation to MPA in the GI tract and absorption to the blood. 19,21) Since MMF is commonly administered in combination with other agents such as calcineurin inhibitors and steroids, many DDIs are reported. For example, co-delivery of cyclosporin A (CysA) can reduce plasma MPA concentration because CysA is believed to inhibit biliary excretion of MPAG, resulting in reduced EHC of MPA.…”

Section: Introductionmentioning

confidence: 99%

Glucuronidation and Subsequent Biliary Excretion of Mycophenolic Acid in Rat Sandwich-cultured Hepatocytes

Tetsuka¹,

Gerst²,

Tamura³

et al. 2014

Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

Rat sandwich-cultured hepatocytes (SCH) were used to correlate the in vitro hepatic disposition of mycophenolic acid (MPA) with published in vivo data, as well as mechanistic studies on drug-drug interaction. The major metabolite of MPA in SCH was 7-O-glucuronide (MPAG) followed by acyl-glucuronide (AcMPAG). MPAG and AcMPAG, but not MPA, showed significant in vitro biliary excretion with biliary excretion indexes (BEI) of 40% for MPAG and 45% for AcMPAG. While these BEIs were similar, the biliary excretion amount (BEA) of MPAG (120 pmol/mg protein) was orders of magnitude higher than that of AcMPAG (0.34 pmol/mg protein). Since MPAG is the major metabolite in in vivo bile, we propose that BEA is a better qualifier of biliary excretion. Quercetin inhibited MPAG and AcMPAG production, while chrysin inhibited only MPAG production, showing that chrysin is not a pan-glucuronidation inhibitor. Cyclosporin A (CysA) reduced the BEI of MPAG and increased intracellular MPA accumulation without changing MPAG amounts. These results suggest that CysA causes inhibition of biliary excretion of MPAG, as well as a mixed inhibition of glucuronidation of MPA and sinusoidal efflux of MPA/MPAG. In conclusion, the present study demonstrates a good agreement of hepatic MPA disposition between SCH and in vivo rats.

show abstract

Section: Introductionmentioning

confidence: 99%

Glucuronidation and Subsequent Biliary Excretion of Mycophenolic Acid in Rat Sandwich-cultured Hepatocytes

Tetsuka¹,

Gerst²,

Tamura³

et al. 2014

Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

show abstract

“…Furthermore, oral MMF administration to Sprague–Dawley (SD) rats yields a recovery of 33% of MPAG, 0.08% of MPA, and 1.06% of AcMPAG in the bile (Gao et al. ). It is also reported that intravenous dosing of MPA to Wistar rats yields 66% of MPAG biliary recovery (Ishizaki et al.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to humans, urinary recovery of MPAG is reported to be only 55% in normal adult Wistar rats (Ishizaki et al 2012) following intravenous injection of MPA. Furthermore, oral MMF administration to Sprague-Dawley (SD) rats yields a recovery of 33% of MPAG, 0.08% of MPA, and 1.06% of AcMPAG in the bile (Gao et al 2011). It is also reported that intravenous dosing of MPA to Wistar rats yields 66% of MPAG biliary recovery (Ishizaki et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Species differences in sinusoidal and canalicular efflux transport of mycophenolic acid 7‐O‐glucuronide in sandwich‐cultured hepatocytes

Tetsuka

Gerst

Tamura

et al. 2014

Pharmacology Res & Perspec

View full text Add to dashboard Cite

Metabolism and sinusoidal/canalicular efflux of mycophenolic acid (MPA) was investigated using sandwich-cultured hepatocytes (SCHs). After applying MPA to SCHs from humans, wild-type rats, and multidrug resistance-associated protein (Mrp) 2-deficient rats, the MPA metabolites 7-O-glucuronide (MPAG) and acyl glucuronide (AcMPAG) were detected in the intracellular compartment of the SCHs. Sinusoidal efflux of MPAG was detected in all SCH preparations including Mrp2-deficient rat SCHs, whereas canalicular efflux of MPAG was observed in wild-type rat and human SCHs but not in Mrp2-deficient rat SCHs. The ratio of canalicular efflux to net (canalicular plus sinusoidal) efflux was 37 ± 8% in wild-type rat SCHs, while the ratio in human SCHs was significantly lower (20 ± 2%, P < 0.05), indicating species differences in the direction of hepatic MPAG transport. This 20% ratio in human SCHs corresponds to a high sinusoidal MPAG efflux (80%) that can in part account for the urine-dominated recovery of MPAG in humans. Both sinusoidal and canalicular MPAG efflux in rat SCHs shows a good correspondence to urinary and biliary recovery of MPAG after MPA dosing. The sinusoidal efflux of AcMPAG in human SCHs was detected from one out of three donors, suggesting donor-to-donor variation. In conclusion, this study demonstrates the predictive value of SCHs for elucidating the interplay of metabolism and efflux transport, in addition to demonstrating a species difference between rat and human in sinusoidal and canalicular efflux of MPAG.

show abstract

“…3 MP is available for oral administration as capsules containing 250 mg and 500 mg. Literature survey reveals, many HPLC [4][5][6] and LC-MS/MS 7-15 based methods have been reported for the determination of MPA in biological samples. Similarly, very few HPLC methods have been reported for the determination of MP alone 16 and in combination with MPA.…”

Section: Introductionmentioning

confidence: 99%

A novel and Rapid LC–MS/MS assay for the Determination of Mycophenolate and Mycophenolic Acid in Human Plasma

Maddela¹,

Pilli²,

Maddela³

et al. 2017

JYP

View full text Add to dashboard Cite

simultaneous determination of mycophenolic acid and its metabolites by HPLC and pharmacokinetic studies in rat plasma and bile

Cited by 17 publications

References 26 publications

Glucuronidation and Subsequent Biliary Excretion of Mycophenolic Acid in Rat Sandwich-cultured Hepatocytes

Glucuronidation and Subsequent Biliary Excretion of Mycophenolic Acid in Rat Sandwich-cultured Hepatocytes

Species differences in sinusoidal and canalicular efflux transport of mycophenolic acid 7‐O‐glucuronide in sandwich‐cultured hepatocytes

A novel and Rapid LC–MS/MS assay for the Determination of Mycophenolate and Mycophenolic Acid in Human Plasma

Contact Info

Product

Resources

About