The effects of P-glycoprotein inhibitor zosuquidar on the sex and time-dependent pharmacokinetics of parenterally administered talinolol in mice

Abstract

P-glycoprotein (P-gp) is an efflux protein that forms a tissue barrier and plays a role in the pharmacokinetics of drugs, limiting the influx of them and other xenobiotics into the cells, as expressed in various tissues such as liver, brain, intestinal mucosa and kidneys. Circadian clock controls many biological functions in mammals including xenobiotic metabolism and detoxification. Circadian rhythms of biological functions may affect the pharmacokinetics, and thus efficacy and/or toxicity of drugs. Aim of this study is to determine how the intraperitoneally administered pharmacokinetics of talinolol, as the probe substrate of P-gp, will change depending on the circadian time and sex in the presence of P-gp inhibitor zosuquidar. 20 mg/kg talinolol with or without 30 mg/kg zosuquidar was administred intraperitoneally to male and female mice at day period (ZT3) and night period (ZT15). Plasma and tissue concentrations of talinolol were determined by using validated HPLC/UV method. The protein levels of P-gp in the liver and small intestine in male and female mice were determined by PCR and Western blot techniques. P-gp protein levels in liver and ileum tissues were not different in female mice but higher in ZT15 as compared to ZT3 in male mice (p<0.05). There was no statistically significant difference in talinolol concentration depending on time and sex in the plasma and liver. There was significant time-dependent difference between ZT3 and ZT15 groups in ileum AUC0–5 h of talinolol (p<0.01). Talinolol plasma and liver AUC0–5 h were increased by zosuquidar administration regardless of dosing-time and sex (p<0.05). Our study findings are considerable in terms of revealing changes in pharmacokinetic profiles of P-gp substrates due to the time of administration in combination with P-gp inhibitors/modulators in managing polypharmacy.