No sex difference in overall P-glycoprotein activity as assessed by talinolol disposition in humans.

PURPOSE: The aim of this study was to investigate the sex-dependent difference in P-glycoprotein activity as measured by the probe drug talinolol. METHODS: A randomized, single-blind, parallel study was carried out in 20 healthy male and 20 healthy female volunteers. The pharmacokinetics of talinolol were measured after single oral dosing of 50-mg tablet and the pharmacokinetic parameters for male and female subjects were compared after excluding the potential influence of P-gp genetic polymorphisms. RESULTS: Talinolol AUC(0-48h) in the female subjects was 23.5% (p = 0.003) higher than that of male subjects. There was no significant sex difference in weight-corrected oral clearance, AUC, or other PK parameters. CONCLUSION: The AUC and other PK data of talinolol, corrected for body weight, did not differ between genders after oral administration. The observed sex difference in talinolol systemic exposure is of little clinical relevance. The overall activity of P-gp shows no sex-related difference.

Design, synthesis, and biological evaluation of dihydroartemisinin-fluoroquinolone conjugates as a novel type of potential antitubercular agents.

Tuberculosis remains a global public health problem in recent years. To develop novel type of potential antitubercular agents, twelve novel dihydroartemisinin-fluoroquinolone (DHA-FQ) conjugates (three types of molecules) were gradually designed and conveniently synthesized. All the newly synthesized conjugates were well characterized and evaluated against different Mycobacterium tuberculosis strains in vitro. The screening results showed that five DHA-FQ conjugates were active toward M. tuberculosis H37Rv, and compound 3a exhibited the strongest inhibitory activity (MIC=0.0625 µg/mL), which was comparable to the positive control Moxifloxacin and even stronger than Ofloxacin. Conjugates 2a and 3a also displayed comparable activities against various clinically isolated sensitive and resistant M. tuberculosis strains (MIC=0.125-16 µg/mL) to Moxifloxacin. All target compounds possessed selective anti-M. tuberculosis ability. Preliminary structure-activity relationship demonstrated that short linker between DHA and FQ was favorable for strong antitubercular activity. This study provides a new clue for the development of novel antitubercular lead molecules.