Examination of the Impact of CYP3A4/5 on Drug-Drug Interaction between Schizandrol A/Schizandrol B and Tacrolimus (FK-506): A Physiologically Based Pharmacokinetic Modeling Approach

Abstract

Schizandrol A (SZA) and schizandrol B (SZB) are two active ingredients of Wuzhi capsule (WZC), a Chinese proprietary medicine commonly prescribed to alleviate tacrolimus (FK-506)-induced hepatoxicity in China. Due to their inhibitory effects on cytochrome P450 (CYP) 3A enzymes, SZA/SZB may display drug-drug interaction (DDI) with tacrolimus. To identify the extent of this DDI, the enzymes' inhibitory profiles, including a 50% inhibitory concentration (IC₅₀) shift, reversible inhibition (RI) and time-dependent inhibition (TDI) were examined with pooled human-liver microsomes (HLMs) and CYP3A5-genotyped HLMs. Subsequently, the acquired parameters were integrated into a physiologically based pharmacokinetic (PBPK) model to quantify the interactions between the SZA/SZB and the tacrolimus. The metabolic studies indicated that the SZB displayed both RI and TDI on CYP3A4 and CYP3A5, while the SZA only exhibited TDI on CYP3A4 to a limited extent. Moreover, our PBPK model predicted that multiple doses of SZB would increase tacrolimus exposure by 26% and 57% in CYP3A5 expressers and non-expressers, respectively. Clearly, PBPK modeling has emerged as a powerful approach to examine herb-involved DDI, and special attention should be paid to the combined use of WZC and tacrolimus in clinical practice.

Keywords: CYP3A5 polymorphism; Wuzhi capsule (WZC); drug–drug interaction (DDI); physiologically based pharmacokinetic (PBPK); schizandrol A (SZA); schizandrol B (SZB); tacrolimus (FK-506).

Figure 1

IC₅₀ values of SZA and SZB in pooled HLMs with and without 30-minute preincubation time. Various concentrations of SZA (0–100 μM) and SZB (0–20 μM) were used. The experiments were conducted in triplicate.

Figure 2

Dixon plots of SZA (A) and SZB (B) on tacrolimus metabolism mediated by CYP3A metabolism in pooled HLMs. Various concentrations of tacrolimus (0.25, 0.5, 1, 2 μM), SZA (0, 4, 8, 16 μM) and SZB (0, 1, 2, 4 μM) were used. Dixon plot of SZB on CYP3A4 (C) and CYP3A5 (D) in genotyped HLMs. Various concentrations of tacrolimus (0.5, 1, 2, 4 μM) and SZB (0, 1, 2, 4 μM) were used. Experiments were conducted in triplicates.

Figure 3

Dixon plots of SZA (A,B) and SZB (C,D) on CYP3A inactivation in pooled HLMs. Various concentrations of SZA (0, 10, 16, 20, 25, 32 μM) and SZB (0, 0.1, 0.2, 0.5, 1, 2 μM) were pre-incubated at 37 °C for 0, 5, 10, 20 and 30 min in 0.1 M PBS. (A,C) were plotted with the log of percentages of control activity versus preincubation time. (B,D) were plotted with the half-life of enzyme inactivation versus the inverse of the SZA or SZB concentration. Each point represents the mean of triplicate experiments.

Figure 4

Dixon plots of SZA on CYP3A4 (A,B) and CYP3A5 (C) inactivation in genotyped HLMs. Various concentrations of SZA (0, 10, 16, 20, 25, 32 μM for CYP3A4 and 0, 10, 20, 30, 40, 50 μM for CYP3A5) were pre-incubated at 3 °C for 0, 5, 10, 20 and 30 min in 0.1 M PBS. (A,C) were plotted with the log of the percentage of control activity versus preincubation time. (B) was plotted with the half-life of enzyme inactivation versus the inverse of the SZA concentration. Each point represents the mean of triplicate experiments.

Figure 5

Dixon plots of SZB on CYP3A4 (A,B) and CYP3A5 (C,D) inactivation in genotyped HLMs. Various concentrations of SZB (0, 0.5, 1, 2, 4, 8 μM for CYP3A4 and 0, 2, 4, 8, 16 μM for CYP3A5) were pre-incubated at 37 °C for 0, 5, 10, 20 and 30 min in 0.1 M PBS. (A,C) were plotted with the log of the percentage of control activity versus preincubation time. (B,D) were plotted with the half-life of enzyme inactivation versus the inverse of the SZB concentration. Each point represents the mean of triplicate experiments.

Figure 6

Simulation of plasma-concentration-time profiles of SZA (A) after a single oral dose of 33.6 mg and SZB (B) after a single oral dose of 10.8 mg in healthy Chinese patients generated by Simcyp^®.

Figure 7

Change in tacrolimus exposure after a single dose of 33.6 mg SZA in CYP3A5 expressers (A) and CYP3A5 non-expressers (B); and after multiple doses of SZA (16.8 mg b.i.d. for 13.5 days) in CYP3A5 expressers (C) and CYP3A5 non-expressers (D).

Figure 8

Change in tacrolimus exposure after a single dose of 10.8 mg SZB in CYP3A5 expressers (A) and CYP3A5 non-expressers (B); and after multiple doses of SZB (5.4 mg b.i.d. for 13.5 days) in CYP3A5 expressers (C) and CYP3A5 non-expressers (D).