Pharmacokinetics of intravenous glycyrrhizin after single and multiple doses in patients with chronic hepatitis C infection

Abstract

Intravenous glycyrrhizin has been used in Japan for the treatment of chronic hepatitis for >20 years, although only a few reports of its pharmacokinetic profile after multiple intravenous doses in small numbers of Japanese patients have been published. The present study compared these Japanese data against the pharmacokinetic characteristics of glycyrrhizin after single and multiple intravenous doses in 35 European patients with chronic hepatitis C infection. We administered 80, 160, or 240 mg glycyrrhizin 3 times/wk or 200 mg glycyrrhizin 6 times/wk for 4 weeks. Twenty-four-hour pharmacokinetic assessments were performed on day 1 and on or around day 14. Glycyrrhizin levels were determined by high-performance liquid chromatography. The mean (+/- SD) volume of distribution at steady state on day 1 in the 80-, 160-, 200-, and 240-mg groups were 67 +/- 11, 62 +/- 13, 54 +/- 7, and 66 +/- 8 mL/kg, respectively. The respective terminal elimination half-lives on day 1 were 7.7 +/- 2.8, 10.1 +/- 1.4, 9.0 +/- 2.3, and 8.6 +/- 2.1 hours. The area under the curve (AUC) increased linearly with doses < or =200 mg (r = 0.67; P < 0.001). No significant differences between day 1 and day 14 were found in any dose group, with the exception of AUC in the 200-mg group, which was significantly higher on day 14 compared with day 1 (P = 0.03). Comparing the European and Japanese data, the mean (+/- SD) AUC was 289 +/- 244 microg/h per mL for the former and 402 +/- 372 microg/h per mL for the latter; the half-life was 8.2 +/- 2.6 versus 8.8 +/- 9.0 hours; and the total clearance was 7.6 +/- 3.6 versus 8.5 +/- 5.7 mL/h per kg. Thus our pharmacokinetic data are comparable to those from Japan. Glycyrrhizin's pharmacokinetics are linear up to 200 mg. Drug accumulation is seen after 2 weeks of treatment with 200 mg administered 6 times/wk.