Journal article
Simultaneous Target-Mediated Drug Disposition Model for Two Small-Molecule Compounds Competing for Their Pharmacological Target: Soluble Epoxide Hydrolase
The Journal of pharmacology and experimental therapeutics, Vol.374(1), pp.223-232
07/2020
DOI: 10.1124/jpet.120.265330
PMCID: PMC7318792
PMID: 32238455
Abstract
1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) and 1-(4-trifluoro-methoxy-phenyl)-3-(1-cyclopropanecarbonyl-piperidin-4-yl)-urea (TCPU) are potent inhibitors of soluble epoxide hydrolase (sEH) that have much better efficacy in relieving nociceptive response than the Food and Drug Administration-approved drug gabapentin in a rodent model of diabetic neuropathy. Experiments conducted in sEH knockout mice or with coadministration of a potent sEH displacer demonstrated that the pharmacokinetics of TPPU and TCPU were influenced by the specific binding to their pharmacologic target sEH, a phenomenon known as target-mediated drug disposition (TMDD). To quantitatively characterize the complex pharmacokinetics of TPPU and TCPU and gain better understanding on their target occupancy, population pharmacokinetics analysis using a nonlinear mixed-effect modeling approach was performed in the current study. The final model was a novel simultaneous TMDD interaction model, in which TPPU and TCPU compete for sEH, with TCPU binding to an additional unknown target pool with larger capacity that we refer to as a refractory pool. The total amount of sEH enzyme in mice was predicted to be 16.2 nmol, which is consistent with the experimental value of 10 nmol. The dissociate rate constants of TPPU and TCPU were predicted to be 2.24 and 2.67 hours
, respectively, which is close to the values obtained from in vitro experiments. Our simulation result predicted that 90% of the sEH will be occupied shortly after a low dose of 0.3 mg/kg TPPU administration, with ≥40% of sEH remaining to be bound with TPPU for at least 7 days. Further efficacy experiments are warranted to confirm the predicted target occupancy. SIGNIFICANCE STATEMENT: Although target-mediated drug disposition (TMDD) models have been well documented, most of them were established in a single compound scenario. Our novel model represents the first TMDD interaction model for two small-molecule compounds competing for the same pharmacological target.
Details
- Title: Subtitle
- Simultaneous Target-Mediated Drug Disposition Model for Two Small-Molecule Compounds Competing for Their Pharmacological Target: Soluble Epoxide Hydrolase
- Creators
- Nan Wu - University of California, DavisBruce D Hammock - University of California, DavisKin Sing Stephen LeeGuohua An - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.374(1), pp.223-232
- DOI
- 10.1124/jpet.120.265330
- PMID
- 32238455
- PMCID
- PMC7318792
- ISSN
- 0022-3565
- eISSN
- 1521-0103
- Grant note
- P42 ES004699 / NIEHS NIH HHS R35 ES030443 / NIEHS NIH HHS
- Language
- English
- Date published
- 07/2020
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984365898602771
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