Identification of human cytochrome P450 isozymes involved in the metabolism of naftopidil enantiomers <i>in vitro</i>

Zhu, Lijun; Liu, Xiawen; Zhu, Liu; Zhang, Xingfei; Fu, Xiaojing; Huang, Junjun; Yuan, Ming

doi:10.1111/jphp.12281

Cited by 8 publications

(6 citation statements)

References 24 publications

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“…Naftopidil in racemic form was provided by Trimax Bio Sciences Ltd. The drug used in clinical practice is the racemate 23 of the free base. Purity of the compound was confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Naftopidil Molecular Salts with Improved Dissolution and Permeation

Mannava

Dandela

Tothadi

et al. 2020

Crystal Growth & Design

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Naftopidil (NFPD) is a α1 adrenoceptor antagonist drug. Low solubility and low permeability are the major drawbacks of this drug. The synthesis of multicomponent crystalline forms of this amine functional group drug with carboxylic acid coformers, both achiral and chiral acids, provides a solution to improve its solubility as well as permeability. Nine molecular salts were crystallized by liquid-assisted grinding followed by isothermal crystallization. Single-crystal X-ray diffraction analysis of the molecular salts showed that the structures are stabilized by strong N–H···O and O–H···O and weak C–H···O hydrogen bonds in the solid state. The bulk phase purity of new solid forms was confirmed by powder X-ray diffraction (PXRD), and the crystalline products were further characterized by IR spectroscopy and thermal analytical techniques (differential scanning calorimetry). The molecular salts exhibit superior dissolution rates compared to pure NFPD. However, during dissolution, NFPD showed decrease in concentration after 60 min for all salts due to precipitation. The supersaturation occurred due to salt disproportionation, which generates insoluble NFPD, as confirmed by PXRD of the residue. The salts reach high saturation concentration before 60 min, which is indicative of immediate release formulation to achieve fast onset of therapeutic activity. Moreover, the salts exhibit high saturation in phosphate buffer saline media and improved permeability compared to the pure drug. Finally, the d,l-malic acid racemate of NFPD shows enhanced dissolution and permeability compared to all other salts and pure NFPD.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Naftopidil Molecular Salts with Improved Dissolution and Permeation

Mannava

Dandela

Tothadi

et al. 2020

Crystal Growth & Design

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“…The liver microsomes, plasma protein binding and a Caco-2 cell monolayer were simultaneously used for studying the mechanism of in vivo drug disposition differences of the chiral drug phencynonate 29,30 . Our results showed that there were significant differences observed in the metabolic stabilities of the two enantiomers of phencynonate in rat liver microsomes.…”

Section: Discussionmentioning

confidence: 99%

Phencynonate S-isomer as a eutomer is a novel central anticholinergic drug for anti-motion sickness

Liu

Wang³

et al. 2019

Sci Rep

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To compare and evaluate the differences of stereoselective activity, the binding affinity, metabolism, transport and molecular docking of phencynonate isomers to muscarinic acetylcholine receptor (mAChR) were investigated in this study. The rotation stimulation and locomotor experiments were used to evaluate anti-motion sickness effects. The competitive affinity with [3H]-QNB and molecular docking were used for studying the interactions between the two isomers and mAChR. The stereoselective mechanism of isomers was investigated by incubation with rat liver microsomes, a protein binding assay and membrane permeability assay across a Caco-2 cell monolayer using a chiral column HPLC method. The results indicated that S-isomer was more effective against motion sickness and had not anxiogenic action at therapeutic doses. S-isomer has the higher affinity and activity for mAChR in cerebral cortex and acted as a competitive mAChR antagonist. The stereoselective elimination of S-isomer was primarily affected by CYP1B1 and 17A1 enzymes, resulting in a higher metabolic stability and slower elimination. Phencynonate S isomer, as a eutomer and central anticholinergic chiral drug, is a novel anti-motion sickness drug with higher efficacy and lower central side effect. Our data assisted the development of a novel drug and eventual use of S-isomer in clinical practice.

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“…Previous studies identified three phase I metabolites and two phase II conjugations in rat plasma containing NAF glucuronides and hydroxyl-NAF glucuronides ( Niebch et al, 1991 ; Li et al, 2006 ). Three phase I metabolites, NHN, PHN, and DMN, required catalytic activity by CYP2C9 and CYP2C19 ( Zhu et al, 2014 ). It was not possible to quantify levels of these metabolites, so contributions of CYP450s and UGTs to the metabolism of NAF remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Three phase I metabolites [(phenyl) hydroxy-NAF (PHN), (naphthyl) hydroxy-NAF (NHN), and O -desmethyl-NAF (DMN)] and two phase II metabolites (NAF and NHN glucuronide conjugates) were identified ( Niebch et al, 1991 ; Li et al, 2006 ). Phase I metabolism of NAF is mediated by cytochrome P450 enzymes (CYP) 2C9 and CYP2C19 ( Zhu et al, 2014 ). Our previous studies indicated the stereoselective pharmacokinetic profiles of NAF enantiomers.…”

Section: Introductionmentioning

confidence: 99%

Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro

Liu

Rong²,

Zhang

et al. 2018

Front. Pharmacol.

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Naftopidil (NAF) is widely used for the treatment of benign prostatic hyperplasia and prevention of prostate cancer in elderly men. These patients receive a combination of drugs, which involves high risk for drug–drug interaction. NAF exhibits superior efficacy but must be administered at a much higher dosage than other therapeutic drugs. We previously showed that extensive glucuronidation of NAF enantiomers caused poor bioavailability. However, the metabolic pathway and mechanism of action of NAF enantiomer remain to be elucidated. The present study was performed to identify the human UDP-glucuronosyltransferases (UGTs) responsible for the glucuronidation of NAF enantiomers and to investigate the potential inhibition of UGT activity by NAF. The major metabolic sites examined were liver and kidney, which were compared with intestine. Screening of 12 recombinant UGTs showed that UGT2B7 primarily contributed to the metabolism of both enantiomers. Moreover, enzyme kinetics for R(+)-NAF, UGT2B7 (mean Km, 21 μM; mean Vmax, 1043 pmol/min/mg) showed significantly higher activity than observed for UGT2B4 and UGT1A9. UGT2B4 (mean Km, 55 μM; mean Vmax, 1976 pmol/min/mg) and UGT2B7 (mean Km, 38 μM; mean Vmax, 1331 pmol/min/mg) showed significantly higher catalysis of glucuronidation of S(-)-NAF than UGT1A9. In human liver microsomes, R(+)-NAF and S(-)-NAF also inhibited UGT1A9: mean Ki values for R(+)-NAF and S(-)-NAF were 10.0 μM and 11.5 μM, respectively. These data indicate that UGT2B7 was the principal enzyme mediating glucuronidation of R(+)-NAF and S(-)-NAF. UGT2B4 plays the key role in the stereoselective metabolism of NAF enantiomers. R(+)-NAF and S(-)-NAF may inhibit UGT1A9. Understanding the metabolism of NAF enantiomers, especially their interactions with metabolic enzymes, will help to elucidate potential drug–drug interactions and to optimize the administration of this medicine.

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Identification of human cytochrome P450 isozymes involved in the metabolism of naftopidil enantiomers in vitro

Abstract: Both R(+)-NAF and S(-)-NAF are metabolized to three metabolites in HLMs. CYP2C9 plays the most important role in the demethylation and hydroxylation of both NAF enantiomers, CYP2C19 is another major CYP isoform that is involved in R(+)-NAF metabolism.

Cited by 8 publications

References 24 publications

Naftopidil Molecular Salts with Improved Dissolution and Permeation

Naftopidil Molecular Salts with Improved Dissolution and Permeation

Phencynonate S-isomer as a eutomer is a novel central anticholinergic drug for anti-motion sickness

Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro

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