Hydrolysis of Capecitabine to 5′-Deoxy-5-fluorocytidine by Human Carboxylesterases and Inhibition by Loperamide

Quinney, Sara K.; Sanghani, Sonal P.; Davis, Wilhelmina I.; Hurley, Thomas D.; Sun, Zejin; Murry, Daryl J.; Bosron, William F.

doi:10.1124/jpet.104.081265

Cited by 163 publications

(128 citation statements)

References 24 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…CES2 is for instance thought to be a main enzyme responsible for the conversion of irinotecan to SN-38 in humans (38), and for hydrolysis of a prodrug of gemcitabine (39). Coadministration of everolimus with ester (pro-) drugs affected by carboxylesterases, including the 5-FU anticancer prodrug capecitabine (40), should thus be assessed very carefully.…”

Section: Discussionmentioning

confidence: 99%

P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice

Tang

Sparidans

Cheung

et al. 2014

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice

Tang

Sparidans

Cheung

et al. 2014

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Carboxylesterases, CES1 and CES2, are responsible for the activation of 2 anticancer prodrugs, capecitabine and irinotecan (38,39). LY2334737 is cleaved only by the CES2 isozyme (11).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Pratt

Durland-Busbice

Shepard

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

LY2334737, an oral prodrug of gemcitabine, is cleaved in vivo, releasing gemcitabine and valproic acid. Oral dosing of mice results in absorption of intact prodrug with slow systemic hydrolysis yielding higher plasma levels of LY2334737 than gemcitabine and prolonged gemcitabine exposure. Antitumor activity was evaluated in human colon and lung tumor xenograft models. The dose response for efficacy was examined using 3 metronomic schedules, once-a-day dosing for 14 doses, every other day for 7 doses, and once a day for 7 doses, 7 days rest, followed by an additional 7 days of once-a-day dosing. These schedules gave significant antitumor activity and were well tolerated. Oral gavage of 6 mg/kg LY2334737 daily for 21 days gave equivalent activity to i.v. 240 mg/kg gemcitabine. HCl administered once a week for 3 weeks to mice bearing a patient mesothelioma tumor PXF 1118 or a non-small cell lung cancer tumor LXFE 937. The LXFE 397 tumor possessed elevated expression of the equilibrative nucleoside transporter-1 (ENT1) important for gemcitabine uptake but not prodrug uptake and responded significantly better to treatment with LY2334737 than gemcitabine (P 0.001). In 3 colon xenografts, antitumor activity of LY2334737 plus a maximally tolerated dose of capecitabine, an oral prodrug of 5-fluorouracil, was significantly greater than either monotherapy. During treatment, the expression of carboxylesterase 2 (CES2) and concentrative nucleoside transporter-3 was induced in HCT-116 tumors; both are needed for the activity of the prodrugs. Thus, metronomic oral low-dose LY2334737 is efficacious, well tolerated, and easily combined with capecitabine for improved efficacy. Elevated CES2 or ENT1 expression may enhance LY2334737 tumor response.

show abstract

“…On the other hand, it was reported that CPT-11 could be hydrolyzed by both CES1A and CES2, but the catalytic efficiency of CES2 is 60-fold higher than that of CES1A (Humerickhouse et al, 2000). In addition, the CPT-11 hydrolase activity at a substrate concentration of 2 M in HLM was potently inhibited by loperamide, which is a selective inhibitor to CES2 (Quinney et al, 2005), with an inhibitor concentration to cause 50% inhibition (IC 50 ) value of 0.46 M (data not shown). Thus, we have judged that flutamide (500 M), imidapril (100 M), and CPT-11 (2 M) could be used as the marker substrates for AADAC, CES1A1, and CES2, respectively.…”

Section: Contributions Of Aadac Ces1a1 and Ces2 To Phenacetin Hydromentioning

confidence: 99%

Arylacetamide Deacetylase Is a Determinant Enzyme for the Difference in Hydrolase Activities of Phenacetin and Acetaminophen

Watanabe

Fukami²,

Takahashi³

et al. 2010

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Phenacetin was withdrawn from the market because it caused renal failure in some patients. Many reports indicated that the nephrotoxicity of phenacetin is associated with the hydrolyzed metabolite, p-phenetidine. Acetaminophen (APAP), the major metabolite of phenacetin, is also hydrolyzed to p-aminophenol, which is a nephrotoxicant. However, APAP is safely prescribed if used in normal therapeutic doses. This background prompted us to investigate the difference between phenacetin and APAP hydrolase activities in human liver. In this study, we found that phenacetin is efficiently hydrolyzed in human liver microsomes (HLM) [CL int 1.08 ؎ 0.02 l/(min ⅐ mg)], whereas APAP is hardly hydrolyzed [0.02 ؎ 0.00 l/(min ⅐ mg)]. To identify the esterase involved in their hydrolysis, the activities were measured using recombinant human carboxylesterase (CES) 1A1, CES2, and arylacetamide deacetylase (AADAC). Among these, AADAC showed a K m value (1.82 ؎ 0.02 mM) similar to that of HLM (3.30 ؎ 0.16 mM) and the highest activity [V max 6.03 ؎ 0.14 nmol/(min ⅐ mg)]. In contrast, APAP was poorly hydrolyzed by the three esterases. The large contribution of AADAC to phenacetin hydrolysis was demonstrated by the prediction with a relative activity factor. In addition, the phenacetin hydrolase activity by AADAC was activated by flutamide (5-fold) as well as that in HLM (4-fold), and the activity in HLM was potently inhibited by eserine, a strong inhibitor of AADAC. In conclusion, we found that AADAC is the principal enzyme responsible for the phenacetin hydrolysis, and the difference of hydrolase activity between phenacetin and APAP is largely due to the substrate specificity of AADAC.

show abstract

Hydrolysis of Capecitabine to 5′-Deoxy-5-fluorocytidine by Human Carboxylesterases and Inhibition by Loperamide

Cited by 163 publications

References 24 publications

P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice

P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Arylacetamide Deacetylase Is a Determinant Enzyme for the Difference in Hydrolase Activities of Phenacetin and Acetaminophen

Contact Info

Product

Resources

About