1. The objective of this study was to investigate the effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism. 2. After oral administration of diammonium glycyrrhizinate (50 mg kg(-1)), the peak plasma concentration (C(max)), area under the plasma concentration-time curve from zero to time tau (AUC(0-tau)), and absolute bioavailability of aconitine (0.2 mg kg(-1)) significantly increased 1.64-, 1.63- and 1.85-fold, respectively, but there was no significant change in half life (t(1/2)) or clearance (CL). In the other two routes of administration via the tail vein and hepatic portal vein, diammonium glycyrrhizinate (15 mg kg(-1)) did not affect any of the pharmacokinetic parameters of aconitine (0.02 mg kg(-1)). Thus, diammonium glycyrrhizinate can enhance the absorption of aconitine, leading to higher oral bioavailability and plasma levels, but it does not influence its elimination. 3. Moreover, an in vitro everted gut sac model and Ussing chamber model were used to investigate the potential mechanism. Results from bidirectional transport and inhibition studies demonstrated that P-glycoprotein was the main efflux transporter involved in the absorption of aconitine in rats. The absorption enhancement effect of diammonium glycyrrhizinate should be mainly attributed to inhibiting the activity of P-glycoprotein rather than to the influence on the paracellular or transcellular transport.

Rifalazil is a new antibiotic structurally related to rifampin but devoid of the metabolic liabilities typically associated with the rifamycin class of antibiotics. A randomized, 3-way crossover study in healthy male volunteers (n = 12) investigated the safety and pharmacokinetics of a single 25-mg oral rifalazil dose administered under a standard breakfast containing fat as 30% of calories, a high-fat breakfast containing fat as 60% of calories, and an overnight fast of 10 hours with a 21- to 28-day washout between doses. Systemic exposure to rifalazil based on Cmax, AUC(0-Tlast), and AUC(0-infinity) was increased progressively as the fat content of the test breakfast was increased from 30% to 60% compared with fasting. The confidence intervals for both fat-containing breakfasts are outside the limits of 80% to 125% allowed for food effect bioequivalence based on Cmax, AUC(0-Tlast), and AUC(0-infinity). This food effect may be a result of increased fractional absorption with increasing dietary fat content. Another striking finding was the large reduction of the pharmacokinetic intersubject variability after rifalazil administration with food. Rifalazil was safe and well tolerated under fed and fasted conditions.