Effect of Severe Renal Dysfunction on the Plasma Levels of DNA-Reactive Platinum after Oxaliplatin Administration

Abstract

Higher amounts of circulating ultrafilterable platinum (fPt) are found in patients with renal dysfunction receiving a constant dose of oxaliplatin. However, the increased systemic fPt levels do not increase oxaliplatin-induced toxicities. We hypothesized that renal dysfunction has minimal effect on the elimination rate of reactive fPt, and that the DNA-binding capacity is one of the properties of reactive Pt species. This study aimed to quantify DNA-reactive fPt in plasma and to evaluate the impact of severe renal dysfunction on its pharmacokinetics. The pharmacokinetics of oxaliplatin was assessed in rats with bilateral nephrectomy (BNx) and in a hemodialysis patient who received mFOLFOX7 therapy for advanced metastatic gastric cancer. The platinum concentrations were determined using inductively coupled plasma-mass spectrometry. The amount of DNA-reactive fPt in the plasma was evaluated by the reaction between plasma and calf thymus DNA. Compared to the sham group in rats, the BNx group had significantly higher plasma total fPt concentrations at 24 h after drug administration. However, there was no significant difference in the plasma levels of DNA-reactive fPt between the two groups. In a hemodialysis patient, the plasma levels of total fPt decreased to 35.9 and 7.3% at 2 and 14 d after treatment, respectively. The plasma level of DNA-reactive fPt also decreased to 1.9 and 0.6%, respectively, on these days. This study showed that severe renal dysfunction has a limited effect on the plasma levels of DNA-reactive fPt after oxaliplatin administration.

INTRODUCTION

Oxaliplatin is a platinum (Pt)-based chemotherapeutic drug that is widely used to treat gastrointestinal and pancreatic cancers. Renal excretion is the main pathway for eliminating oxaliplatin-derived Pt from the body, and there is a significant correlation between creatinine clearance and plasma clearance of ultrafilterable platinum (fPt) in patients administered with oxaliplatin.^1–4) Thus, at a constant dose of oxaliplatin, patients with impaired renal function have higher amounts of circulating fPt^2–4); nonetheless, the increased systemic fPt levels do not increase oxaliplatin-induced hematological, neurological, and digestive toxicities.^2–5) It has been reported that the area under the concentration-time curves of fPt are not associated with the changes in leucocytes, neutrophils, and platelets counts in patients administered with oxaliplatin.⁴⁾ In addition, the apparent clearance of oxaliplatin-derived fPt is markedly reduced in hemodialysis patients; however, this does not increase the risk of adverse events.^6–8) The reason for these results may be that plasma fPt consists of reactive as well as inactive Pt species,^9–11) and the kidney does not significantly contribute to the elimination of this reactive fPt.^4,12) However, this hypothesis remains unproven because the previous studies in patients with renal dysfunction have been based only on plasma levels of total fPt.

According to previously published reports, oxaliplatin is a DNA-reactive drug, and the formation of the Pt-DNA complex contributes to its cytotoxicity.^13,14) The oxaliplatin-DNA complexes are formed when the oxalate group of oxaliplatin is replaced by chloride or water to generate highly reactive Pt species in blood and tissues, and then cause cytotoxicity.^10,15,16) The formation of oxaliplatin-DNA complexes with naked DNA in a buffer can also be observed in vitro, where the chlorination of oxaliplatin occurs.¹⁷⁾ Based on the above studies, we assumed that the DNA-binding capacity was one of the properties of reactive Pt species. Initially, we attempted to develop a method to quantify DNA-reactive fPt by reacting plasma ultrafiltrate with naked DNA. We then evaluated the contribution of the kidney to the plasma levels of DNA-reactive fPt derived from oxaliplatin using an animal model. Furthermore, we examined the time course of plasma concentrations of total Pt, total fPt, and DNA-reactive fPt in a hemodialysis patient.

MATERIALS AND METHODS

Animals

Eight-week-old male Wistar/ST rats were purchased from SLC Animal Research Laboratories (Shizuoka, Japan) and maintained according to the guidelines for Animal Experiments of Kyoto University, Kyoto, Japan. The study design was approved by the Animal Research Committee of the Graduate School of Medicine, Kyoto University, Kyoto, Japan (Permit Nos. Medkyo 20122 and 21114). The rats were housed in a specific pathogen-free facility, maintained in a temperature-controlled environment with a 12-h light/dark cycle, and fed a standard diet and water ad libitum.

Reaction of Oxaliplatin with Calf Thymus DNA

Initially, we assessed the time dependence of the reaction between oxaliplatin and calf thymus DNA as per a previous report.^17,18) The oxaliplatin (Wako Pure Chemical Corporation, Osaka, Japan) was dissolved in N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid (HEPES) buffer (10 mM, pH 7.4; Nacalai Tesque, Kyoto, Japan) to prepare 1.26 nmol/mL oxaliplatin solution. Then, an aliquot of 50 µL oxaliplatin solution was mixed with HEPES buffer (10 mM, pH 7.4) containing 0.56 mg/mL calf thymus DNA (Sigma-Aldrich, St. Louis, MO, U.S.A.) and 56 mM NaCl (Nacalai Tesque) in a 1 : 9 ratio. The reaction mixture was incubated at 37 °C for 1, 2, 4, 6, 24, or 48 h. After incubation, DNA was extracted from the solution using phenol : chloroform : isoamyl alcohol (25 : 24 : l; Nippon Gene, Tokyo, Japan). The extracted DNA was dried, resuspended in ultrapure water, and incubated overnight at 4 °C. To determine the DNA concentration, absorbance was measured at 260, 280, and 320 nm using UV spectrometry (NanoDrop, Thermo Fisher Scientific Inc., MA, U.S.A.). After adding an equivalent volume of 60% HNO₃ (Wako Pure Chemical Corporation), the DNA solution was heated at 95 °C for 1 h and then diluted 6-fold with ultrapure water. The Pt concentration was determined using inductively coupled plasma-mass spectrometry (ICP-MS; Agilent7700/MassHunter, Agilent Technologies, CA, U.S.A.).

We then assessed the substrate concentration dependence of this reaction. Different concentrations of oxaliplatin solutions (0.0126, 0.04, 0.126, 0.4, 1.26, 4, and 12.6 nmol/mL) were prepared to react with calf thymus DNA, and Pt complexed with DNA was quantified as described above. The concentration of DNA-reactive Pt in each sample was expressed as the amount of Pt present in 1 mL of the sample complexed to calf thymus DNA in 1 h (pmol/mL/h).

To assess the effect of plasma ultrafiltrate on the production of the Pt-DNA complex, oxaliplatin solutions (0.126, 1.26, and 12.6 nmol/mL) were prepared by diluting the oxaliplatin (5 mg/mL, 5% glucose) in HEPES buffer (10 mM, pH 7.4), rat plasma or human plasma ultrafiltrates. Human plasma was purchased from Kojin Bio (Saitama, Japan). Plasma ultrafiltrates were obtained by centrifuging the plasma using ultrafiltration membranes (Amicon Ultra-0.5 mL, 30 kDa filter; Merck-Millipore, Darmstadt, Germany). Then, different concentrations of oxaliplatin were made to react with calf thymus DNA and the Pt complexed to DNA was quantified as described above.

Reaction of fPt Present in Rat Plasma with Calf Thymus DNA

Rats were anesthetized (using medetomidine, midazolam, and butorphanol) and maintained on a digital temperature controller (TC-1000; As One, Osaka, Japan) at 37 °C. Catheters were inserted into the left femoral vein and the right femoral artery using polyethylene tubing (SP-31; Natsume Seisakusho, Tokyo, Japan). Then, oxaliplatin was infused (5 mg/mL, 5% glucose) via the femoral vein at a constant rate of 2 mg·h⁻¹·kg⁻¹ for 1 h using an automatic infusion pump (Natsume Seisakusho). Blood samples (0.5 mL) were obtained from the femoral artery at the end of administration and 5, 15, 30, and 60 min after administration. Whole blood was centrifuged at 10000 × g for 5 min at room temperature to obtain plasma. The plasma was transferred to an ultrafiltration device and centrifuged at 10000 × g for 5 min at room temperature. Plasma was obtained within 15 min of blood collection. Ultrafiltration of the plasma and reaction with calf thymus DNA were performed immediately afterward. Plasma levels of DNA-reactive fPt were quantified as described above. The total Pt concentration in plasma (total Pt) and its ultrafiltrate (total fPt) were determined by the following method: 450 µL of 60% HNO₃ was added to 50 µL of sample. The mixed solution was heated at 95 °C for 1 h, then further diluted 10 times with ultra-pure water. The Pt concentration in each sample was measured using ICP-MS.

Pharmacokinetics of Oxaliplatin in Bilaterally Nephrectomized Rats

We adapted bilateral nephrectomy (BNx) as a mechanistic experimental manipulation to determine whether the kidney contributes the plasma levels of DNA-reactive fPt after oxaliplatin administration. Rats were anesthetized (using medetomidine, midazolam, and butorphanol), and their kidneys were exposed via a ventral abdominal incision under aseptic conditions. Both kidneys were removed by ligating the renal pedicles with 4-0 silk sutures (BNx group). Then, the abdominal incision was closed with 4-0 silk sutures. As a control, the rats were anesthetized and subjected to a sham operation (sham group). Subsequently (under anesthesia), catheters were inserted into the left femoral vein and the right femoral artery using polyethylene tubing. Then, the oxaliplatin (5 mg/mL, 5% glucose) was infused via the femoral vein at a constant rate of 2 mg·h⁻¹·kg⁻¹ (for the sham group) and 1 mg·h⁻¹·kg⁻¹ (for the BNx group) for 1 h using an automatic infusion pump. Blood samples were obtained from the femoral artery at the end of the administration and 1 and 24 h after administration. The rats were allowed to recover from anesthesia 1 h after the start of oxaliplatin administration but were anesthetized again (using medetomidine, midazolam, and butorphanol) for subsequent blood sampling and tissue collection. Since most of the rats in the BNx group did not survive till 48 h after surgery, the observation was limited to 24 h. Plasma levels of total Pt, total fPt, and DNA-reactive fPt were quantified as described above. The total Pt concentration in tissues was determined using the following method: the tissue was homogenized using nine volumes of saline. Then, 450 µL of 60% HNO₃ was added to 50 µL of the suspension. The mixed solution was heated at 95 °C for 1 h and diluted 10 times with ultra-pure water. The Pt concentration in each sample was measured using ICP-MS.

Statistical analysis was performed using the GraphPad Prism version 8.0 software (GraphPad, San Diego, CA, U.S.A.). The data on the plasma levels of total Pt, total fPt, and DNA-reactive fPt were analyzed using Bonferroni’s multiple comparisons test after two-way or repeated measures ANOVA. The data on Pt levels in tissues were analyzed using an unpaired t-test. A p-value <0.05 was considered-statistically significant.

Pharmacokinetics of Oxaliplatin in a Hemodialysis Patient

The study was conducted in accordance with the principles of the Declaration of Helsinki and its amendments. The Ethics Committee of Kyoto University approved the study protocol (E2178). Plasma levels of Pt were measured in a 63-year-old man who had been on dialysis for 5 years because of nephrosclerosis. He was diagnosed with an advanced metastatic gastric cancer and was treated with modified FOLFOX7 (m FOLFOX7) plus trastuzumab chemotherapy. Blood samples were collected during the third treatment cycle. The treatment schedule was as follows: on day 1, 85 mg/m² oxaliplatin and 200 mg/m² L-leucovorin were administered by intravenous infusion over 2 h; 1600 (cycle 1 and 3) or 2000 (cycle 2) mg/m² fluorouracil was administered by continuous intravenous infusion over 46 h (from day 1 to 3). Dexamethasone and granisetron were administered prior to these. The treatment cycle lasted 14 d, but trastuzumab (4 mg/m²) was started in the second cycle and administered at 3-week intervals. Oxaliplatin was administered on a non-dialysis day. Dialysis was performed the day after oxaliplatin administration and three times per week thereafter. Informed consent was obtained from the patient to participate in the study. Blood samples were collected at the end of oxaliplatin administration in the third cycle and after day 2 and day 14. Plasma was obtained by centrifugation within 15 min of the blood collection. Then, ultrafiltration of the plasma and its reaction with calf thymus DNA were performed immediately. Plasma levels of total Pt, total fPt, and DNA-reactive fPt were quantified as described above.

RESULTS

Development of a Method to Evaluate Plasma Levels of DNA-Reactive fPt

The amount of DNA-Pt complex, reactant of oxaliplatin with calf thymus DNA, increased along with reaction time (Fig. 1A) and substrate (Fig. 1B) concentration. This reaction was not inhibited in the presence of human and rat plasma ultrafiltrates (Fig. 1C). When 1.26 nmol/mL oxaliplatin was reacted with DNA for 24 h, 45.5 ± 4.4% of Pt in the sample solutions complexed to DNA.

Fig. 1. The Reaction between Oxaliplatin or Ultrafilterable Platinum in Rat Plasma with Calf Thymus DNA

The amount of DNA-platinum (Pt) complex produced by the reaction between oxaliplatin and calf thymus DNA increased with time (A) and the substrate concentration (0.0127–12.7 nmol/mL) (B). The reaction was not inhibited by the presence of human and rat plasma ultrafiltrate (C). Therefore, we used blood samples to quantify total Pt in plasma, Pt in plasma ultrafiltrates (total fPt), and fPt with DNA-binding capacity (DNA-reactive fPt) (D). In rats, the amount of DNA-reactive fPt is positively correlated with the plasma fPt concentration (E and F, correlation coefficient = 0.98). Data are expressed as mean ± standard deviation (S.D.) (n = 3). ICP-MS, inductively coupled plasma-mass spectrometry.

We then attempted to quantify total fPt and DNA-bound fPt using rat plasma (Fig. 1D), and examined the correlation between the plasma levels of DNA-reactive fPt and total fPt in vivo (Figs. 1E, F). The results showed that the amount of DNA-reactive fPt was positively correlated with plasma total fPt concentration (Fig. 1E, correlation coefficient = 0.98). After 24 h of reaction, an average of 40.6 ± 7.3% fPt complexed with calf thymus DNA. This result was comparable to that of the intact oxaliplatin.

Decrease in the DNA-Reactive fPt in BNx Rats after Oxaliplatin Administration

Next, we evaluated the role of the kidney in the pharmacokinetics of oxaliplatin in rats with BNx or sham operations. BNx was selected as a model for complete loss of renal function. We found that rats with normal renal function excreted an approximate half of the dose (2 mg/kg oxaliplatin) of Pt during 1 h of continuous infusion (data not shown). To allow the plasma Pt levels at the end of administration to be equivalent between the experimental groups and compare subsequent changes, oxaliplatin at doses of 2 and 1 mg/kg were administered to the sham and BNx rats, respectively. At the end of the drug administration and after 1 h, the levels of plasma total Pt and fPt were comparable between these groups; however, these values significantly increased in the BNx group compared to those in the sham group, at 24 h after drug administration (Figs. 2A, B). In the sham group, the unbound fraction of Pt decreased over time, but in the BNx group, it increased for 24 h after the drug administration (Fig. 2C). However, there was no significant difference (p = 0.43 with a repeated measures ANOVA) in the plasma levels of DNA-reactive fPt between the two groups (Fig. 2D). When the plasma ultrafiltrates at the end of the oxaliplatin administration were reacted with DNA for 24 h, 43.4 ± 5.8% (the sham grops) and 43.6 ± 7.8% (the BNx group) of fPt complexed to DNA (p = 0.96). In the plasma ultrafiltrates at 24 h after the drug administration, the percentages of fPt complexed to DNA were 49.4 ± 29.8 and 1.7 ± 1.1% in the sham and BNx groups, respectively (p < 0.01). Assuming that almost all plasma fPt at the end of oxaliplatin administration was reactive and that the concentrations of DNA-reactive fPt correlated with the total concentrations of reactive fPt, we estimated the plasma levels of reactive and inactive fPt at each time point (Fig. 2E). The majority of plasma fPt in the sham group was reactive, whereas the majority of plasma fPt in the BNx group was inactive. We also examined Pt levels in the rat liver and spleen 24 h after oxaliplatin administration (Fig. 2F). The amount of Pt in the liver but not in the spleen was significantly higher in the BNx group than in the sham group. The ratio between the tissue and plasma concentrations of total Pt (Kp) was significantly lower in the BNx group than in the sham group (Fig. 2G).

Fig. 2. Pharmacokinetics of Oxaliplatin in Rats

Plasma levels of total Pt (A), total fPt (B), and DNA-reactive fPt (D) were determined after oxaliplatin administration in male Wistar/ST rats subjected to bilateral nephrectomy (BNx) or sham operation (sham). The unbound fraction was calculated as the ratio of fPt to Pt (C). Assuming that almost all plasma fPt at the end of oxaliplatin administration was reactive and that the concentrations of DNA-reactive fPt correlated with the total concentrations of reactive fPt, the plasma levels of reactive and inactive fPt were estimated (E). Pt levels in the liver and spleen 24 h after oxaliplatin administration (F) and ratios between the tissue and plasma concentrations of total Pt (Kp) (G) were also evaluated. Data are expressed as mean ± S.D. (n = 5). ** p < 0.01 represents a significant difference between the two groups.

Decrease in the DNA-Reactive fPt in a Hemodialysis Patient after Oxaliplatin Administration

We investigated the pharmacokinetics of oxaliplatin in a hemodialysis patient who received mFOLFOX7 therapy for advanced metastatic gastric cancer (Fig. 3). At the end of oxaliplatin administration, the plasma levels of total Pt, total fPt, the unbound fraction of Pt, and DNA-reactive fPt were 14.2, 6.6 nmol/mL, 46.3%, and 96.8 pmol/mL/h, respectively (Figs. 3A, B). However, the plasma levels of total Pt, fPt, and the unbound fraction decreased to 8.0, 2.4 nmol/mL, and 29.7%, respectively, at two days after drug administration; and 2.6, 0.5 nmol/mL, and 18.7%, respectively, at 14 d after administration. The plasma level of DNA-reactive fPt decreased to 1.8 pmol/mL/h at 2 d and 0.6 pmol/mL/h at 14 d after treatment. The percentages of DNA-reactive fPt among total fPt at the end of the drug administration, 2 and 14 d after that were 35,3, 1.9, and 3.2%, respectively (percentages determined by the 24-h reactions). The plasma levels of reactive and inactive fPt were estimated, assuming that almost all plasma fPt at the end of oxaliplatin administration was reactive and that the concentrations of DNA-reactive fPt correlated with the total concentrations of reactive fPt (Fig. 3C). The majority of plasma fPt was inactive. In this case, peripheral neuropathy and fatigue (both grade 1) were observed during 14–16 d after oxaliplatin administration during the third cycle of mFOLFOX7 therapy. However, the clinical data after the third cycle of therapy were within the normal range (Table 1).

Fig. 3. Pharmacokinetics of Oxaliplatin in a Hemodialysis Patient

The plasma levels of total Pt, total fPt (A), and DNA-reactive fPt (B) in a male dialysis patient administered oxaliplatin on the non-dialysis day. The plasma levels of reactive and inactive fPt were estimated, assuming that almost all plasma fPt at the end of oxaliplatin administration was reactive and that the concentrations of DNA-reactive fPt correlated with the total concentrations of reactive fPt (C).

Table 1. Changes in Laboratory Data after the Third Cycle of mFOLFOX7

	Days after the administration of oxaliplatin
	0	14
Estimated glomerular filtration rate (mL/min/1.73 m2)	5.8	5.4
White blood cell (103 cells/µL)	5.04	4.13
Platelet (103 cells/µL)	176	114
Hemoglobin (g/dL)	11.1	10.7
Albumin (g/dL)	3.6	3.7

DISCUSSION

Oxaliplatin is a key drug in the treatment of advanced gastrointestinal and pancreatic cancers. However, the effect of renal dysfunction on the pharmacokinetics and pharmacodynamics of this Pt-based drug has not been fully defined. In particular, no clinical and preclinical studies have evaluated the effect of renal dysfunction on the pharmacokinetics of oxaliplatin-derived reactive Pt. Therefore, the present study was conducted to quantify the plasma levels of DNA-reactive fPt in nephrectomized rats and in a hemodialysis patient. We, for the first time, discovered that severe renal function has no significant effect on the level of DNA-reactive fPt in plasma after oxaliplatin administration.

We found that oxaliplatin-derived plasma fPt in rats with normal renal function had DNA binding capacity equivalent to that of oxaliplatin. This result suggests that most plasma fPt exists as either oxaliplatin or reactive Pt species when renal function is normal. This is consistent with previous reports that the major form of Pt in the plasma is oxaliplatin, and only less than 3% of it is biotransformed into the dichloro complex for at least the first few hours following oxaliplatin infusion in humans.^9,19) We also found that severe renal dysfunction did not significantly affect the plasma levels of total Pt, total fPt, or DNA-reactive fPt in rats for 1 h after oxaliplatin administration. These results, together with previous reports,^4,12) suggested that the decrease in the level of DNA-reactive fPt from plasma in the early phase after oxaliplatin administration was mainly due to its binding to plasma proteins and uptake into red blood cells or tissues. In contrast, renal dysfunction eventually resulted in delayed fPt elimination and increased its unbound fraction, but did not affect plasma levels of DNA-reactive fPt. This result might be due to the presence of inactive Pt species, such as cysteine-, methionine-, or glutathione-Pt conjugates^11,15,20) in plasma, which have small volumes of distribution. Alternatively, because renal function affects the plasma concentrations of various amino acids and organic acids,^21–23) it is possible that unique metabolites are produced, or the conversion of oxaliplatin to its inactive metabolites is altered in patients with renal dysfunction. Future studies are warranted to identify these Pt complexes in the blood of patients.

At a constant dose of oxaliplatin, patients with impaired renal function are likely to have higher total fPt levels than those with normal renal function.^2–4) In dialysis patients, administration of oxaliplatin results in a dramatic increase in the total fPt levels.^6,7) However, this increase in fPt exposure does not significantly increase the risk of adverse reactions.^2–7,24) This is probably because the elimination of reactive fPt from plasma is faster than that of total fPt. In the present patient requiring hemodialysis, the plasma level of DNA-reactive fPt decreased to 1.9% at 48 h after oxaliplatin administration, while the plasma level of total fPt decreased to 35.9%. This change in the plasma levels of DNA-reactive fPt was comparable to that in rats and the change in total fPt in patients with normal renal function. In rats, the plasma levels of DNA-reactive fPt decreased by 36.0 ± 20.9% from 1 to 24 h after oxaliplatin administration. Assuming a similar or slower rate of decline after that, the plasma levels of DNA-reactive fPt in rats at 48 h after the administration would be 0.9 ± 1.0% (relative to the value immediately after the administration) or higher. Based on the pharmacokinetic models developed in previous studies,^1,25–27) in patients with normal renal function, plasma levels of total fPt would decrease to 1.6–7.7% in 48 h after the oxaliplatin administration. Taken together, it is suggested that renal function had an insignificant effect on the plasma levels of DNA-reactive fPt. In the present patient, the percentage of DNA-reactive fPt in total fPt decreased to less than one-tenth in two days. Moreover, the present case showed no severe adverse reactions due to oxaliplatin, suggesting that the plasma levels of total fPt are not a marker of the pharmacodynamics activity of oxaliplatin in dialysis patients.

This study had several limitations. First, we only evaluated the DNA-binding capacity of Pt as a measure of pharmacodynamic activity. Second, we did not quantify intact oxaliplatin and its metabolites. Since there could be various biotransformation products of oxaliplatin in the blood, it is not feasible to quantify each of them. Thus, we recommend that it would be more reasonable to quantify reactive Pt species than each metabolite individually. Third, BNx is associated not only with acute kidney injury but also with several physiological changes. In particular, it has been reported that 24 h after BNx, the albumin concentration in the serum decreases to approximately 90%.²⁸⁾ As we did not measure these physiological parameters in this study, it remains possible that unmeasured factors may have influenced our results. Fourth, only one hemodialysis patient was included in the study. Fifth, concomitant drugs may have affected the pharmacokinetics of oxaliplatin in the present case. In particular, drugs that alter the protein binding of Pt may affect plasma levels of DNA-reactive fPt. However, the effects of fluorouracil, levofolinate, trastuzumab, dexamethasone, and granisetron are considered small. On the other hand, we could not collect data on drugs prescribed at other hospitals. To generalize the present findings, evaluation of DNA-reactive Pt after oxaliplatin administration with larger sample sizes and the effects of concomitant drugs should be done in the future.

In summary, this study showed that renal dysfunction has a limited effect on the plasma levels of DNA-reactive fPt after oxaliplatin administration. However, further studies are warranted to clarify the feasibility of oxaliplatin-based therapy in patients with renal dysfunction, especially those on hemodialysis.

Acknowledgments

This work was supported by Grant-in-aid from the Research Foundation for Pharmaceutical Sciences to Shunsaku Nakagawa.

Author Contributions

Contribution to study design and its implementation: SN, TF, AY, MY, MM, KM, TT; Data analysis and interpretation: SN, AS, TF, AY, SK, TH, DH, KI, SI, TK, MY, MM, KM, TT; Manuscript writing and editing: SN, AS, TF, AY SK, TH, DH, KI, SI, TK, MY, MM, KM, TT. All authors read and approved the final version of the manuscript.

Conflict of Interest

TF belongs to an endowed chair sponsored partly by Yakult Honsha Co., Ltd. MY has received research Grants from Mitsubishi Tanabe Pharma and Boehringer Ingelheim. The other authors declare that they have no conflict of interest.

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