Research ArticleExperimental Studies

Optimal Administration of Glycyrrhizin Avoids Pharmacokinetic Interactions With High-dose Methotrexate and Exerts a Hepatoprotective Effect

YASUNARI MANO, KENTARO ABE, MIO TAKAHASHI, TSUKASA HIGURASHI, YOHEI KAWANO, SATORU MIYAZAKI and AYAKO MAEDA-MINAMI
Anticancer Research April 2023, 43 (4) 1493-1501; DOI: https://doi.org/10.21873/anticanres.16298

Abstract

Background/Aim: Glycyrrhizin (GZ) is widely used to treat high-dose methotrexate (MTX)-induced liver dysfunction. However, in a previous in vivo study, we showed that simultaneous administration of both drugs increased the plasma concentration of MTX and exacerbated hepatic injuries. In this study, we investigated the optimal dosing interval in rats to avoid the interaction between high-dose MTX and GZ and to demonstrate the inherent hepatoprotective effect of GZ. Materials and Methods: Male Wistar rats were treated with high-dose MTX (2,000 mg/kg) alone, with concomitant administration of 100 mg/kg GZ or GZ administered 3, 6, and 24 h before MTX administration. Plasma concentrations of MTX, alanine aminotransferase, aspartate aminotransferase, and total bilirubin were measured. Results: The plasma concentration and half-life of methotrexate were significantly increased after concomitant administration of GZ, or when GZ was administered 3 h before MTX administration, compared with MTX alone, increasing hepatic enzyme levels. However, when GZ was administered 6 and 24 h before MTX administration, the levels were not significantly different from those of MTX alone and showed a tendency to decrease MTX-induced liver injury. These results suggest that the pharmacokinetic interaction between GZ and MTX could be avoided and the hepatoprotective effect of GZ could be achieved by an optimal dosing regimen, using the half-life of GZ as an indicator. Conclusion: When using high-dose MTX in combination with GZ, the administration intervals should be considered to avoid unwanted interactions and to achieve the GZ hepatoprotective effect.

Key Words:

Methotrexate (MTX) inhibits cell proliferation by preventing the production of tetrahydrofolate, which produces the active folate needed for nucleic acid synthesis, and inhibits the thymidylate and purine synthesis systems (1, 2). High-dose methotrexate therapy (HD-MTX), defined as a dose of 500 mg/m2 or higher, is used to treat osteosarcoma, acute leukemia, and malignant lymphoma (3). Various side effects of HD-MTX have been reported, including myelosuppression, renal dysfunction, oral mucosal disorders, and hepatic dysfunction (3). Among these side effects, hepatic dysfunction occurs with high incidence due to elevated levels of hepatic transaminases, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (4-6). Although this is a common side effect, these function parameters are only transiently elevated and rarely result in chronic liver disease or severe cases (7). However, in patients with liver dysfunction, it is necessary to reduce the dose or discontinue treatment with MTX and postpone scheduled chemotherapy and surgery, resulting in significant interruptions in the treatment schedule (8).

When HD-MTX-induced liver dysfunction occurs, leucovorin dosage is increased and glycyrrhizin (GZ) is used for treatment. GZ has anti-inflammatory and anti-allergic effects (9) and acts as a hepatoprotective agent, improving liver function. It is also widely used for the treatment of other diseases, such as pruritus and urticaria (10, 11). Studies conducted in vivo have reported that the administration of GZ affects the plasma levels of MTX (12). However, in that report, the dosage was low, and the route of administration was oral, assuming a low dose of methotrexate as in clinical use for rheumatoid arthritis (12). In a previous study, we investigated the pharmacokinetic interaction between HD-MTX and GZ in rats, using a dose and route of administration similar to those of HD-MTX in humans. We demonstrated that concomitant administration of HD-MTX and GZ increased the plasma concentration of MTX, resulting in elevated liver function parameters, suggesting the possibility of exacerbating liver injury (13). Therefore, it is necessary to elucidate the optimal relationship between the dosing interval of MTX and the concomitant administration of GZ and MTX plasma concentration, and how this affects liver function.

In this study, we investigated the optimal dosing interval to avoid the interaction between HD-MTX and GZ and to demonstrate the hepatoprotective effect of GZ in rats, considering the clinical dosage and route of administration.

Materials and Methods

Chemicals. Chloroform, acetonitrile, isoflurane, and 0.5 M sodium hydroxide solution were purchased from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan). Glycyrrhizin and methotrexate hydrate were manufactured by Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). The saline solution was purchased from Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan).

Animals and drug administration. Male Wistar rats (9 weeks old; mean body weight=205.40 g) were purchased from Sankyo Labo Service Co., Inc. (Tokyo, Japan) and fasted overnight, with drinking water ad libitum, before the experiments. In a preliminary experiment, the dose of MTX administered intravenously to induce liver dysfunction in rats was found to be 2,000 mg/kg; this dose was used in this study. Rats were divided into groups treated with MTX alone, MTX and GZ concurrently, and MTX and GZ combination groups: GZ 3 h pretreatment, GZ 6 h pretreatment, and GZ 24 h pretreatment groups in which GZ was administered 3, 6, and 24 h, respectively, before the administration of MTX. Under isoflurane anesthesia, all administrations were performed intravenously, with normal saline administered rapidly at 2 ml/kg, followed by MTX (2,000 mg/kg) at 17.6 ml/kg for 10 min in the MTX alone group. In the MTX and GZ concurrent group, GZ (100 mg/kg) was administered rapidly at 2 ml/kg, followed by MTX (2,000 mg/kg) at 17.6 ml/kg for 10 min. In the MTX and GZ combination groups, GZ (100 mg/kg) was administered rapidly at 2 ml/kg 3, 6, and 24 h before the administration of MTX (2,000 mg/kg), for each pretreatment group. The volume of fluid administered was the same in all groups. Animal experiments were performed following the protocol reviewed by the Institutional Animal Care and Use Committee and approved by the President of the Tokyo University of Science (approval number Y21035).

Blood sample collection. Approximately 0.35 ml of blood was collected from the jugular vein 1 min, 30 min, 1 h, 4 h, 6 h, 8 h, and 24 h after administration of MTX to measure MTX blood levels. Approximately 0.85 ml of blood was collected from the jugular vein 5 min before and 4, 6, 8, and 24 h after administration of MTX to measure hepatic function. The collected blood samples were centrifuged (4 °C, 11,000 × g, 10 min), and plasma was collected and stored at −30°C until measurement.

Analytical methods. Serum MTX concentrations were determined according to the method described by Montemurro et al. (14) with slight modifications. Briefly, 300 μl of acetonitrile was added to 150 μl of plasma. The mixture was vortexed for 30 s, centrifuged (4°C, 11,000 × g, 3 min), and 350 μl of the supernatant was collected. Chloroform (300 μl) was added to the supernatant, and the mixture was vortexed for 30 s. Next, 50 μl of the supernatant were collected, and 20 μl were injected into a high-performance liquid chromatography (HPLC) system, consisting of a Poroshell 120 EC-C18 separation column [3.0×75 mm, 2.7 μm; Agilent Technologies, Inc. (Santa Clara, CA, USA)]. The mobile phase used was 85 mM acetate buffer (pH 4.0): acetonitrile=88.8:11.2 v/v, under isocratic conditions. The temperature of the column was 25°C, the flow rate was 0.4 ml/min, and detection was performed using a UV detector at 305 nm. The limit of quantification of MTX in rat serum was 0.2 μM.

Determination of hepatic data. Measurements of hepatic function parameters [AST, ALT, and total bilirubin (T-Bil)] were conducted at SRL Co., Ltd. (Tokyo, Japan) using the obtained plasma.

Data analysis. Serum concentrations of MTX were analyzed using a two-compartment model. The disposition of MTX is described in terms of the biexponential equation C=Ae−αt +Be−βt. A and B are the zero-time intercepts of phase α and β-extrapolations, respectively. Total clearance (CLt) was calculated using the following formula: CLt=Dose/(AUC0 + A/α + B/β), where AUC0 is the area under the blood concentration curve during drug infusion (10 min) calculated from the triangular area. Vc is the apparent volume of distribution in the central compartment. Vβ is the apparent volume of distribution in the β-phase (also referred to as the post-distributional phase). Vdss is the apparent volume of distribution at steady state.

All results are expressed as mean±standard deviation (SD). Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by Dunnett’s test to compare different parameters in each group. IBM SPSS Statistics 23 (IBM, Tokyo, Japan) were used for statistical analyses. The statistical significance level was set at p<0.05.

Results

Effect of plasma concentration-time profiles of methotrexate at different intervals of administration between methotrexate and glycyrrhizin in rats. To determine whether the dosing interval between MTX and GZ affects pharmacokinetics, the changes in plasma concentration-time courses were evaluated. Figure 1 shows the plasma concentration-time profiles after intravenous administration of MTX for each group. The pharmacokinetic parameters are listed in Table I. In the MTX and GZ concurrent combination group, a significant increase in the plasma concentration of MTX was observed after 4 h of administration of MTX compared to that in the MTX alone group. In the GZ and MTX combination group, a significant increase in the plasma concentration of MTX was observed only in the GZ 3 h pretreatment group at 4 and 6 h after administration of MTX compared with that in the MTX alone group. No significant difference was observed in the GZ 6 and 24 h pretreatment groups compared with that in the MTX alone group. In terms of pharmacokinetic parameters, a significant prolongation of the half-life of the β phase (t1/2β), a significant decrease in CLt, and a significant increase in AUC were observed in the MTX and GZ concurrent combination group compared with those in the MTX alone group. The GZ 3 h pretreatment group showed a significant prolongation of t1/2β compared with that observed in the MTX alone group. Similar to the plasma concentration-time profiles, there was no significant difference in pharmacokinetic parameters in the GZ 6 h and 24 h pretreatment groups compared with that in the MTX alone group.

Figure 1.
Figure 1.

Plasma concentration-time curve of methotrexate (MTX) in rats after intravenous administration of MTX in each group. Each data point represents the mean±S.D. of three rats. Significantly different at **p<0.01, *p<0.05 vs. MTX alone (one-way ANOVA followed by Dunnett’s multiple comparisons test). MTX: Methotrexate; GZ: glycyrrhizin.

View this table:
Table I.

Pharmacokinetic parameters of methotrexate (MTX) after intravenous administration at 2,000 mg/kg in the MTX alone group, the MTX and 100 mg/kg glycyrrhizin (GZ) concurrent combination group, and MTX and GZ combination groups: GZ 3 h pretreatment, GZ 6 h pretreatment, and GZ 24 h pretreatment groups.

Effect of changes in dosing interval between methotrexate and glycyrrhizin on hepatic data in rats. The time course of hepatic function parameters (AST, ALT and T-Bil) after intravenous administration of MTX (2,000 mg/kg) alone, co-administration of MTX and GZ (100 mg/kg) simultaneously, or a combination of MTX and GZ at intervals in rats are shown in Figure 2, Figure 3, and Figure 4, respectively.

Figure 2.
Figure 2.

Plasma concentration-time profiles of aspartate aminotransferase (AST) in rats after intravenous administration of methotrexate (MTX) in each group. The inset is the enlarged figure of the AST value in the range between 0-250 U/l. Each point represents the mean±SD of three rats. Significantly different at **p<0.01; *p<0.05 vs. MTX alone (one-way ANOVA followed by Dunnett’s multiple comparisons test). GZ: Glycyrrhizin.

Figure 3.
Figure 3.

Plasma concentration-time profiles of alanine aminotransferase (ALT) in rats after intravenous administration of Methotrexate (MTX) in each group. The inset is the enlarged figure of the ALT value in the range between 0-200 U/l. Each point represents the mean±SD of three rats. Significantly different at **p<0.01; *p<0.05 vs. MTX alone (one-way ANOVA followed by Dunnett’s multiple comparisons test). GZ: Glycyrrhizin.

Figure 4.
Figure 4.

Plasma concentration-time profiles of total bilirubin (T-Bil) in rats after intravenous administration of MTX in each group. The inset is the enlarged figure of the T-Bil value in the range between 0-0.07 U/l. Each point represents the mean±SD of three rats. Significantly different at **p<0.01; *p<0.05 vs. MTX alone (one-way ANOVA followed by Dunnett’s multiple comparisons test). GZ: Glycyrrhizin.

Levels of AST and ALT in rats treated with MTX alone were transiently elevated 4 h after administration of MTX and were 2.7- and 2.8-fold higher, respectively, than levels in untreated control rats. In addition, significant increases in all hepatic function parameters (AST, ALT, and T-Bil) were observed in the MTX and GZ concurrent combination group and the GZ 3 h pretreatment group, when compared with that in the MTX alone group. The highest levels of AST were observed at 8 h after administration of MTX in these groups, with an approximately 90-fold increase in the MTX and GZ concurrent combination group and an approximately 65-fold increase in the GZ 3-h pretreatment group when compared with that in the MTX alone group. ALT values were highest at 6 h after administration of MTX in both groups, with an approximately 70-fold increase in the MTX and GZ concurrent combination group and an approximately 55-fold increase in the GZ 3 h pretreatment group when compared with that in the MTX alone group. T-Bil levels were highest 8 h after administration of MTX in both groups, approximately 40-fold higher in the MTX and GZ concurrent combination group and approximately 35-fold higher in the GZ 3 h pretreatment group than in the MTX alone group. In contrast, the GZ 6 hours pretreatment group and GZ 24 hours pretreatment group showed a tendency to reduce MTX-induced liver injury. In fact, liver function tests (AST and ALT) at 4 hours after MTX administration were approximately 0.6- and 0.4-fold lower in the GZ 6-h pretreatment group than in the MTX alone group, respectively. In the GZ 24-h pretreatment group, both AST and ALT levels decreased approximately 0.6-fold. In the GZ 24 h pretreatment group, both AST and ALT levels decreased by approximately 0.6-fold.

Discussion

In our previous study of pharmacokinetic interaction between HD-MTX and GZ in rats, we showed that simultaneous administration of both drugs increased the plasma concentration of MTX and exacerbated hepatic injuries (13). However, there are only a few studies about how to avoid pharmacokinetic interactions. In the present study, we investigated the optimal dosing interval to determine whether HD-MTX and GZ could avoid pharmacokinetic interactions and whether GZ can exert its intrinsic hepatoprotective effect in rats in a manner reflecting the clinical dosing and route of administration. The results showed that simultaneous administration of MTX (2,000 mg/kg) and GZ significantly prolonged t1/2β, decreased CLt, increased the AUC of MTX compared with MTX alone, and prolonged t1/2β when GZ was administered 3 h before MTX administration. In addition, with concomitant administration of GZ, or 3 h before administration of MTX, an increase in the plasma concentration of MTX and a simultaneous increase in the hepatic function parameters AST, ALT, and T-Bil, was observed. This suggests that the administration of GZ concomitantly with or 3 h before MTX may exacerbate hepatic injury by affecting the pharmacokinetics of MTX and reduce the elimination of MTX. However, there was no increase in the plasma concentration of MTX after the administration of GZ 6 or 24 h before the administration of MTX, and no significant differences were observed in pharmacokinetic parameters compared with the administration of MTX alone. Furthermore, when GZ was administered 6 or 24 h before the administration of MTX, the levels of AST and ALT decreased compared with the levels when MTX was administered alone. This suggests that MTX and GZ administered more than 6 h apart may avoid pharmacokinetic interactions and exhibit intrinsic hepatoprotective effects in rats. To the best of our knowledge, this is the first study to demonstrate an optimal GZ dosing regimen to reduce liver injury during HD-MTX therapy in rats, reflecting its clinical use.

The clinical dose of HD-MTX is 8-12 g/m2 (15-18), which corresponds to a dose of 100-300 mg/kg per week in patients with osteosarcoma and 30-100 mg/kg per week in patients with lymphoma and leukemia. In our previous study on the pharmacokinetic interaction between MTX and GZ, rats were administered 500 and 1,000 mg/kg MTX (13), whereas, in this study, the dose was 2,000 mg/kg. The dose was calculated using the allometric formula (19), which is used to convert doses for humans and rats. Using this formula, doses of 30-100 mg/kg and 100-300 mg/kg in humans correspond to 182-620 mg/kg and 620-1,860 mg/kg, respectively, when converted to doses for rats. Considering a clinical dose of HD-MTX for patients with osteosarcoma of 140-350 mg/kg, from a previous report (20), the animal dose for a case in which 350 mg/kg was used in clinical practice was converted to 2,170 mg/kg with this formula. Therefore, the MTX dose (2,000 mg/kg) administered to rats in this study was approximately equivalent to HD-MTX in humans. The dose of GZ (100 mg/kg) corresponds to what has been used in clinical practice (21). The reason for the higher dose of MTX (2,000 mg/kg) in this study, compared with our previous studies with MTX and GX in rats (500 mg/kg and 1,000 mg/kg) is that the dose of MTX alone was chosen to cause hepatotoxicity before evaluating the hepatoprotective effect of GZ. Indeed, levels of AST and ALT were transiently elevated in rats treated with MTX alone 4 h after administration and were 2.7- and 2.8-fold higher, respectively, than in untreated control rats, indicating that MTX-induced hepatic dysfunction occurred after administration of MTX at a dose of 2,000 mg/kg.

Compared with that in the MTX alone group, plasma concentrations of MTX increased significantly in the MTX and GZ concurrent combination group and the group treated with GZ 3 h before administration of MTX, and a concomitant increase in liver function test values was observed. The present pharmacokinetic interaction results in rats support two studies; our previous in vivo results (13) and a retrospective study using medical records (22) that suggested delayed MTX excretion when GZ and HD-MTX were combined. MTX is poorly metabolized in the liver, and its main route of excretion is renal while it is also excreted in bile. Multiple transporters, such as breast cancer resistance protein 1 (BCRP1) and multidrug resistance-associated protein 2 (MRP2), which belong to the ABC transporter family, are thought to be involved in MTX excretion (23, 24). While MTX is excreted via the biliary excretion transporter MRP2 (25), GZ has been reported to inhibit MRP2, suggesting that it may inhibit MTX excretion (12). Glycyrrhizic acid (GA), a metabolite of GZ, has also been reported to inhibit BCRP1 and MRP2 (12). Therefore, we consider that both GZ and GA inhibit the biliary excretion of MTX, resulting in delayed excretion, which may exacerbate hepatic injuries.

When GZ was administered 6 or 24 h before the administration of MTX, no delayed excretion of MTX was observed, indicating a tendency to reduce MTX-induced hepatic dysfunction. These results suggest that the pharmacokinetic interaction between MTX and GZ could be avoided, and the original hepatoprotective effect of GZ could be achieved by administering appropriate dosing intervals for both drugs. The main pharmacological activity of GZ is considered to be its metabolite GA. Previous studies reported low plasma GA concentrations after intravenous administration of GZ (100 mg/kg), maintained until 50 h, because of the enterohepatic circulation in rats (26). Based on the results of this study, it appears that the pharmacokinetic interaction between GZ and MTX is stronger than the hepatoprotective effect of GA with a high plasma level of GZ within 3 h after GZ administration, while the hepatoprotective effect of GA is stronger than the pharmacokinetic interaction between both drugs at 6 h after GZ administration due to the decrease in the plasma level of GZ (Figure 5). The half-life of GZ (100 mg/kg) administered intravenously to rats was reported to be 4.68 hours (27). An interaction occurred when GZ was administered 3 h before MTX was administered, i.e., MTX was administered before the half-life of GZ had passed after GZ administration. However, when GZ was administered 6 or 24 h before the administration of MTX, these interactions were avoided. This suggests that the half-life of GZ may be an indicator of the optimal dosing interval for both drugs. Nevertheless, the differences in MTX metabolism and excretion in humans and rats must be considered (28). The biliary excretion rate of MTX has been reported in previous studies to range from 3 to 26% in humans (29-31), whereas it has been reported to be approximately 50% in rats (32). Considering the species differences, the pharmacokinetic interaction between MTX and GZ needs to be elucidated in future studies.

Figure 5.
Figure 5.

Relationship between pharmacokinetic interactions and liver protective effects due to differences in administration intervals between Methotrexate (MTX) and Glycyrrhizin (GZ), the timing of administration of MTX, and simulation of plasma concentration-time curve of GZ and glycyrrhizic acid (GA) after intravenous administration of GZ. t1/2: Half-life.

Conclusion

In conclusion, we have demonstrated a useful dosing method for GZ when used in combination with HD-MTX in a basic experiment in rats. We have shown that concomitant administration of GZ with HD-MTX significantly increases plasma levels of MTX and decreases its clearance for excretion, resulting in hepatic dysfunction. However, this pharmacokinetic interaction can be avoided, and the hepatoprotective effect of GZ could be achieved by administering MTX after the half-life period of GZ. Based on this, when HD-MTX is used in combination with GZ, more attention should be paid to changes observed in the function tests, as liver injury may be exacerbated depending on the dosing interval. GZ and MTX should be administered at appropriate dosing intervals to avoid interactions and to achieve the inherent hepatoprotective effects of GZ. We believe this study will help determine the appropriate dosing intervals between GZ and MTX in clinical practice.

Footnotes

  • Authors’ Contributions

    Y.M., K.A., M.T. and T.H. performed the experiments; Y. M., K.A., M.T. and T.H. conceived the study; K.A., M.T., T.H. and S.M. conducted the statistical analysis; Y.M. and A.M.-M. drafted the manuscript; Y.M., K.A., M.T., T.H., Y. K., S.M. and A.M.-M. contributed to the discussion and review of the final article. All Authors approved the final article and contributed to its discussion and review.

  • Conflicts of Interest

    The Authors declare no potential conflicts of interest.

  • Received January 15, 2023.
  • Revision received January 30, 2023.
  • Accepted February 6, 2023.

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Optimal Administration of Glycyrrhizin Avoids Pharmacokinetic Interactions With High-dose Methotrexate and Exerts a Hepatoprotective Effect
YASUNARI MANO, KENTARO ABE, MIO TAKAHASHI, TSUKASA HIGURASHI, YOHEI KAWANO, SATORU MIYAZAKI, AYAKO MAEDA-MINAMI
Anticancer Research Apr 2023, 43 (4) 1493-1501; DOI: 10.21873/anticanres.16298
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