This study assessed the effects of the traditional Chinese medicine WZC on Tac blood concentrations in 185 LT patients with different combinations of donor-recipient CYP3A5 genotypes. The major novel findings were as follows: (1) Donor-recipient CYP3A5 genotypes significantly affected the Tac blood concentrations, with the lowest C0, C0/D, and C0/D/W observed in the R+/D + group on days 7 and 14 after LT; (2) Tac blood levels were significantly elevated by the use of WZC in LT patients in the R+/D+, R+/D-, and R-/D + groups; (3) Greater increases in the C0/D and C0/D/W were significantly associated with higher doses of WZC; (4) The use of WZC reduced the need for Tac dose adjustment, especially in the R+/D+, R+/D-, and R-/D + groups.
Tac is a powerful immunosuppressant that is widely used for patients who undergo solid organ transplantation (8). However, the narrow therapeutic window of Tac presents a clinical challenge. For instance, too low a dose can lead to rejection, and too high a dose can cause drug-induced toxicity (15). Therefore, the target C0 is generally set at 5–10 ng/ml (16) and the oral dose of Tac is adjusted according to the blood concentration. Tac is mainly metabolized by CYP3A4 and CYP3A5 in the liver and small intestine, while P glycoprotein, a product of the multidrug resistance 1 gene (MDR1) or the so called ATP-binding cassette (ABC) transporter, ABCB1, limits the absorption of Tac by pumping it out of the cell (16, 17). Due to the low frequency of polymorphisms, it is difficult to attribute large pharmacokinetic changes to the CYP3A4 genotype alone (18), and no significant difference between the high- and low-CYP3A4 groups in Tac dosage or the C/D ratio has been reported (16). Although intra-individual variations in the C0/D ratio are closely related to the expression level of MDR1, there is no significant relationship between the C3435T single nucleotide polymorphism (SNP) in the MDR1 gene and the pharmacokinetics of Tac (16) and the impact of the SNP is rather limited (19, 20).
Previous studies have demonstrated that the variations of the CYP3A5 genotypes largely contribute to Tac disposition (20–22). The SNP in intron 3 of the CYP3A5 gene (CYP3A5*3, g.6986A > G, rs776746) can cause splicing errors and abnormal splicing of mRNA to stop codons prematurely, thereby deactivating enzymes (1). Many previous studies have reported the significant impact of CYP3A5*3 SNPs on the pharmacokinetics of Tac, causing the enzyme to lose its activity (16, 23, 24). In CYP3A5 expressers, the weight-corrected Tac daily dose requirements and weight-corrected steady-state clearance were ~ 1.8-fold higher, while the dose-corrected C0 and AUC0–12 were ~ 2.0-fold lower than those of CYP3A5 non-expressers (25). Intestinal CYP3A5 and hepatic CYP3A5 play important roles in the oral clearance of Tac (16). In this study, according to the donor-recipient CYP3A5 genotypes, the185 LT recipients were divided into four groups: R+/D + group, R+/D- group, R-/D + group, R-/D- group. The different combinations represented the intestinal and hepatic CYP3A5 activity. We found that the C0/D and C0/D/W in the R+/D + group were the lowest among the groups on the 7th day, while the C0/D and C0/D/W of the R-/D- group were significantly higher than those of the other three groups on the 14th day. These findings are consistent with previous studies (16, 24), indicating that either the intestinal enzyme activity or the liver enzyme activity improved on day 14 after LT. Unlike the intestinal CYP3A5 enzyme, which is responsible for stronger Tac metabolism than the liver CYP3A5 enzyme in the early stages after LDLT as reported previously (11, 26), this study has shown that the C0, C0/D, and C0/D/W of the R+/D- and R-/D + groups are not significantly different on days 7 and 14 after LT. This indicates that the CYP3A5 enzymes in the intestine and liver have no significant differences in Tac metabolism in the early stages after LT.
WZC is a traditional Chinese medicine extracted from Schisandra sphenanthera and is widely used to treat liver damage caused by hepatoxins, viral hepatitis, or acetaminophen (9, 10, 27). Its active ingredients are schisandrins (A, B, C), schisandrols (A, B), and schisantherins (A, B) (28). Qin et al reported that the lignans in WZC and Tac were both substrates of CYP3A, the affinity of the WZC lignans to CYP3A was much higher than that of Tac, and WZCs successfully competed against Tac with a much stronger metabolism (29). Studies in rats and healthy volunteers have demonstrated that the active ingredients of WZC may increase the oral bioavailability of Tac and maintain its blood concentration by inhibiting the metabolism of CYP3A-mediated Tac and the P glycoprotein-mediated efflux of Tac (11, 14). Co-administration of Wuzhi tablet significantly reduced the Tac dose requirements without impairing its immunosuppressive effect (30). In the present study, we explored the potentially beneficial effects of WZC in patients with different donor-recipient CYP3A5 genotypes. On day 7 after LT, the C0/D and C0/D/W in the R+/D + group were significantly lower than the values in the other three groups. On day 14, the C0/D and C0/D/W of the R-/D- group was significantly higher than those of the other three groups. It may merit attention that the use of WZC diminished the difference in Tac metabolism caused by variations in the CYP3A5 genotypes, thereby reducing the required dose of Tac in the enzyme expression groups (R+/D+, R+/D-, and R-/D + groups).
Qin and colleagues reported that the AUC value after oral Tac dosing increased by 2.1 fold and that the oral bioavailability (Foral) of Tac increased from 5.4–13.2% when co-administered with WZC (11). In this study, we observed that WZC significantly increased the C0, C0/D, and C0/D/W on day 14 compared with the values on day 7. It can be concluded that WZC can significantly increase the blood concentration of Tac and has a superimposing effect; that is, increasing the dose of WZC can further increase the blood concentration of Tac.