precision-induction-distinction-coughing-sneezing-reflexes

Precision Induction and Distinction of Coughing and Sneezing Reflexes in Mice

Coughing and sneezing, as vital respiratory defensive reflexes, have seen research into their mechanisms constrained by the nonspecific stimulation ...

Guangzhou Medical University

Naftopidil (NAF) is used as a racemate to treat benign prostatic hyperplasia (BPH) and to prevent prostate cancer. However, racemic NAF has low bioavailability; therefore, it is commonly administered at higher clinical dosages compared to other therapeutic BPH drugs. Differences in interactions between individual enantiomers and biological macromolecules may result in variations in pharmacokinetics and dispositions. This study aimed to investigate the pharmacokinetics, bioavailability and tissue distributions of NAF enantiomers in rats after intragastric administration of the individual enantiomers. A rapid and sensitive liquid chromatography coupled with triple-quadrupole mass spectrometric method (RRLC-MS/MS) was developed and validated for determination of NAF enantiomers in rat plasma, tissues, urine and feces. After intragastric administration, S(-)-NAF in plasma [maximum concentration (C(max)) = 186.4 ng/mL, area under the curve from 0 h to 24h (AUC(0-24 h)) = 877.9 ng h/mL] was significantly higher than that of R(+)-NAF (C(max) = 133.2 ng/mL, AUC(0-24 h) = 602.1 ng h/mL). Moreover, S(-)-NAF bioavailability was twice that of R(+)-NAF. R(+)-NAF distributions in the prostate, liver, and kidney were significantly higher than S(-)-NAF distributions (R/S ratios of 3.16, 1.33, and 2.90, respectively). These data reveal the stereoselective pharmacokinetic profiles of the two enantiomers in rats.

Enantiospecific determination of naftopidil by RRLC-MS/MS reveals stereoselective pharmacokinetics and tissue distributions in rats.

Racemic naftopidil (NAF) is used to treat benign prostatic hyperplasia (BPH) and prostatic cancer (PCa). It exhibits greater efficacy but requires higher dose than other ɑ1-adrenoceptor blockers because of its poor bioavailability. It was previously shown that bioavailability of S(-)-NAF (14.5%) was twice that of R(+)-NAF (6.8%). The present study aimed to elucidate the major factors contributing to the poor and enantioselective bioavailability of NAF. First, absorption of NAF enantiomers was examined using a perfusated intestinal model. NAF enantiomers were found to be equally and highly permeable in all segments of the intestine. Second, the metabolites formed in different parts of the intestine and in bile were investigated. Glucuronidation of NAF enantiomers was found to occur primarily in the liver. Third, a new method consisting of ultra performance liquid chromatography coupled with triple-quadruple mass spectrometry (UPLC-MS/MS) was employed to quantify and calculate the pharmacokinetic parameters of NAF enantiomers and their glucuronides after the enantiomers were intravenously injected into rats. The amounts of R(+)-NAF glucuronide (R(+)-NAF-G) and S(-)-NAF glucuronide (S(-)-NAF-G) were six-fold higher than that of R(+)-NAF, and three-fold higher than that of S(-)-NAF. Glucuronidation of S(-)-NAF was faster than that of R(+)-NAF, but the conjugated amount was half of that of R(+)-NAF. Thus, bioavailability of S(-)-NAF was twice that of R(+)-NAF. In conclusion, extensive phase II metabolism in the liver significantly contributes to the low bioavailability of NAF enantiomers. Glucuronidation is the most important metabolic pathway for NAF enantiomers. Glucuronidation of S(-)-NAF is faster but occurs to a lesser extent than that of R(+)-NAF.

Poor and enantioselective bioavailability of naftopidil enantiomers is due to extensive and stereoselective metabolism in rat liver.

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 , 21 μM; mean , 1043 pmol/min/mg) showed significantly higher activity than observed for UGT2B4 and UGT1A9. UGT2B4 (mean , 55 μM; mean , 1976 pmol/min/mg) and UGT2B7 (mean , 38 μM; mean , 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  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.

Article	Year
Enantiospecific determination of naftopidil by RRLC-MS/MS reveals stereoselective pharmacokinetics and tissue distributions in rats. Journal of pharmaceutical and biomedical analysis\| PubMed ID: 25985066	2015
Poor and enantioselective bioavailability of naftopidil enantiomers is due to extensive and stereoselective metabolism in rat liver. Journal of pharmaceutical and biomedical analysis\| PubMed ID: 27744175	2017
Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation . Frontiers in pharmacology\| PubMed ID: 29375383	2017

Rong Yi

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