Involvement of Carboxylesterase 1 and 2 in the Hydrolysis of Mycophenolate Mofetil

Fujiyama, Nobuhiro; Miura, Masatomo; Kato, Shoutaro; Sone, Tomomichi; Isobe, Masakazu; Satoh, Shigeru

doi:10.1124/dmd.110.034249

Cited by 70 publications

(41 citation statements)

References 25 publications

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“…Because these agents are activated by CES1, a possible mechanism for this lack of effect could be the simultaneous administration of immunosuppressive drugs that inhibit CES1. A previous study demonstrated that the immunosuppressive agent, mycophenolate mofetil, was a substrate for CES1 (Fujiyama et al, 2010). Other immunosuppressive agents have not been tested for their activity as esterase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…The enzyme is involved in the metabolism of several therapeutic agents, drugs of abuse, and endogenous compounds. CES1 activates several ester-containing prodrugs, including oseltamivir, dabigatran etexilate, mycophenolate mofetil, and a number of angiotensin-converting enzyme (ACE) inhibitors, including trandolapril, imidapril, benazepril, and quinapril (Takai et al, 1997;Shi et al, 2006;Zhu et al, 2009;Fujiyama et al, 2010;Hu et al, 2013). The enzyme also inactivates a multitude of drugs, including methylphenidate, pethidine, clopidogrel, rufinamide, and oxybutynin (Zhang et al, 1999;Sun et al, 2004;Tang et al, 2006;Williams et al, 2011;Sato et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

2013

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Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensinconverting enzyme inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1-and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

2013

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“…CMBL is a relatively novel hydrolysis enzyme, and any potential overlap in its substrates with CES is not well characterized. Cellular localization of these enzymes differs, as CES are present both in the membrane and cytosol (Satoh and Hosokawa, 1998;Fujiyama et al, 2010) whereas CMBL is a predominantly cytosolic enzyme (Ishizuka et al, 2013), emphasizing the need for a careful choice of in vitro system for adequate characterization of hydrolysis. In addition, paraoxonase 1 (PON1), predominantly located in plasma (Bahar et al, 2012), hydrolyzes lactones and aromatic carboxylic acid esters (Fukami and Yokoi, 2012;Ishizuka et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Hepatic, Intestinal, Renal, and Plasma Hydrolysis of Prodrugs in Human, Cynomolgus Monkey, Dog, and Rat: Implications for In Vitro–In Vivo Extrapolation of Clearance of Prodrugs

2014

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Hydrolysis plays an important role in metabolic activation of prodrugs. In the current study, species and in vitro system differences in hepatic and extrahepatic hydrolysis were investigated for 11 prodrugs. Ten prodrugs in the data set are predominantly hydrolyzed by carboxylesterases (CES), whereas olmesartan medoxomil is also metabolized by carboxymethylenebutenolidase (CMBL) and paraoxonase. Metabolic stabilities were assessed in cryopreserved hepatocytes, liver S9 (LS9), intestinal S9 (IS9), kidney S9 (KS9), and plasma from human, monkey, dog, and rat. Of all the preclinical species investigated, monkey intrinsic hydrolysis clearance obtained in hepatocytes (CL int,hepatocytes ) were the most comparable to human hepatocyte data. Perindopril and candesartan cilexetil showed the lowest and highest CL int,hepatocytes , respectively, regardless of the species investigated. Scaled intrinsic hydrolysis clearance obtained in LS9 were generally higher than CL int,hepatocytes in all species investigated, with the exception of dog. In the case of human and dog intestinal S9, hydrolysis intrinsic clearance could not be obtained for CES1 substrates, but hydrolysis for CES2 and CMBL substrates was detected in IS9 and KS9 from all species. Pronounced species differences were observed in plasma; hydrolysis of CES substrates was only evident in rat. Predictability of human hepatic intrinsic clearance (CL int,h ) was assessed for eight CES1 substrates using hepatocytes and LS9; extrahepatic hydrolysis was not considered due to high stability of these prodrugs in intestinal and kidney S9. On average, predicted oral CL int,h from hepatocyte data represented 20% of the observed value; the underprediction was pronounced for highclearance prodrugs, consistent with the predictability of cytochrome P450/conjugation clearance from this system. Prediction bias was less apparent with LS9, in particular for high-clearance prodrugs, highlighting the application of this in vitro system for investigation of prodrugs.

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“…MMF metabolizes into MPA in the liver, and it is non-competitive and a reversible inhibitor of IMP dehydrogenase enzyme, resulting in the inhibition of the de novo pathway of guanine nucleotide synthesis. This directly diminishes the proliferation of T and B lymphocytes and also suppresses antibody formation [4,5]. Prednisolone, chemically known as (8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-7, 8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-one is a glucocorticoid that has anti-infl ammatory action [6,7].…”

Section: Introductionmentioning

confidence: 98%

Development and Validation of a Novel Dual Wavelength UV-Spectrophotometric Method for the Simultaneous Estimation of Mycophenolate Mofetil and Prednisolone

Kaur

Sharma

Namdev³

et al. 2014

J Appl Spectrosc

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A dual wavelength UV-spectrophotometric method has been developed for the simultaneous estimation of mycophenolate mofetil and prednisolone. In this method two wavelengths were selected for the estimation of each drug in such a way that the difference in the absorbance was zero for the second drug on the respective wavelength for the fi rst drug. This method was selected because of the overlapping of the absorbance maxima of the drugs. Prednisolone has equal absorbance value at wavelengths 235.11 and 261.33 nm; therefore, these two wavelengths were used to determine the concentration of mycophenolate mofetil in the combination. Similarly, 270.3 and 277.4 nm wavelengths were selected to determine the concentrations of prednisolone, where mycophenolate mofetil was observed with equal absorbance values. Regression analysis for the method shows good correlation in the concentration ranges 10-50 μg/ml for mycophenolate mofetil and 2-10 μg/ml for prednisolone. The method was validated using parameters provided as per ICH guidelines.

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Involvement of Carboxylesterase 1 and 2 in the Hydrolysis of Mycophenolate Mofetil

Cited by 70 publications

References 25 publications

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

Hepatic, Intestinal, Renal, and Plasma Hydrolysis of Prodrugs in Human, Cynomolgus Monkey, Dog, and Rat: Implications for In Vitro–In Vivo Extrapolation of Clearance of Prodrugs

Development and Validation of a Novel Dual Wavelength UV-Spectrophotometric Method for the Simultaneous Estimation of Mycophenolate Mofetil and Prednisolone

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