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

Abstract

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.

In Vitro Hepatic Assessment of Cineole and Its Derivatives in Common Brushtail Possums (Trichosurus vulpecula) and Rodents

“…CYP3A inhibition activities using cineole and its derivatives were further predicted with DL-CYP Prediction server [ 16 ]. This is a web-based tool that predicts the inhibition tendency of small molecules on five major CYP isoforms, namely CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.…”

Naftopidil Molecular Salts with Improved Dissolution and Permeation

“…8 Because of these factors, the dosage of NFPD (brand name Flivas) is much higher (25−75 mg/d) than other pharmaceutical therapies used to treat BPH, such as tamsulosin (0.2 mg/d), terazosin (1−5 mg/d), and finasteride (5 mg/d). 8 An amorphous solid dispersion approach by using cyclodextrin complex was investigated to improve NFPD dissolution rate, while the potential of this approach is limited because of limited solubility enhancement. 6 Thus, there is a need for finding a better approach to improve NFPD solubility and permeation properties.…”

“…It has been claimed that the central nervous system is the general target to treat both the diseases through α 1 -adrenoreceptor, where NFPD plays a vital role to treat both diseases simultaneously without adverse effect; moreover, it is convenient for patient compliance, cost, and safety . But, NFPD is a biopharmaceutics classification system (BCS) class IV , drug with very low solubility (0.11 mg mL –1 ) and low permeability at intestinal pH (log P 3.77, Drug Bank), which results in poor oral bioavailability, that is, 20% in humans because of rate-limiting permeation in first-pass metabolism . Because of these factors, the dosage of NFPD (brand name Flivas) is much higher (25–75 mg/d) than other pharmaceutical therapies used to treat BPH, such as tamsulosin (0.2 mg/d), terazosin (1–5 mg/d), and finasteride (5 mg/d) .…”

“…But, NFPD is a biopharmaceutics classification system (BCS) class IV , drug with very low solubility (0.11 mg mL –1 ) and low permeability at intestinal pH (log P 3.77, Drug Bank), which results in poor oral bioavailability, that is, 20% in humans because of rate-limiting permeation in first-pass metabolism . Because of these factors, the dosage of NFPD (brand name Flivas) is much higher (25–75 mg/d) than other pharmaceutical therapies used to treat BPH, such as tamsulosin (0.2 mg/d), terazosin (1–5 mg/d), and finasteride (5 mg/d) . An amorphous solid dispersion approach by using cyclodextrin complex was investigated to improve NFPD dissolution rate, while the potential of this approach is limited because of limited solubility enhancement .…”

Absence of significant association between UGT2B4 genetic variants and the susceptibility to anti‐tuberculosis drug‐induced liver injury in a Western Chinese population

“…In addition, UGTs are some of the most important metabolic enzymes in the second phase of drug metabolism in the liver. Because UGT2B4 is capable of catalyse glucuronidation of catechol estrogens, phenols and hyodeoxycholic acid,28 it has been shown to be involved in the metabolism of drugs such as Naftopidil,29 Salvia miltiorrhiza Bunge30 and so on. FXR, which controls the balance of BAs by regulating their synthesis, detoxification and transport, has been studied in the many drug metabolism pathways involved in UGT2B4 .…”