- Email: [email protected]
Tripterygium Wilfordii Hook F Increase the Blood Concentration of Tacrolimus
Tripterygium Wilfordii Hook F Increase the Blood Concentration of Tacrolimus J. Wen, L. Li, J. Chen, S. Ji, C. Zheng, and Z. Liu ABSTRACT Objective. To observe the influence of the Tripterygium wilfordii Hook F (T II) on the blood concentration of tacrolimus and analyze the impact of this effect. Method. Twenty-two renal transplant receipts taking tacrolimus combined with the T II were selected for this study. We analyzed the blood concentrations and the rate of concentration compared with dosage (C/D rate) pre- and postcombination over 6 months. All cases underwent the CYP3A5 genotype test. Result. The concentrations of tacrolimus were raised to a certain degree after the combination in all the cases. The first-time elevation differed from 1 week to 4 months. The C/D rate increased by 1.7 to 7.2 times with most evaluated C/D rates ranging from 1.8 to 3.8. The elevated C/D rate of the subgroup of CYP3A5 1*/1* and 1*/*3 (n ⫽ 10) contrasted with the *3/*3 genotype subgroup (n ⫽ 12: 2.99 ⫾ 1.71 vs 2.55 ⫾ 1.07; P ⫽ .472). The mycophenolate mofetil subgroup (n ⫽ 17) was not contrasted to the mizoribine subgroup (n ⫽ 5: 2.85 ⫾ 1.51 vs 2.31 ⫾ 0.26; P ⫽ .498). Conclusion. T II considerably increased the blood concentration and the C/D rate of tacrolimus. The degree of increase was probably not related to the CYP3A5 genotype and the combination of immunosuppressive agents.
T
ACROLIMUS IS AN EFFECTIVE immunosuppressant for organ transplantation, especial in renal and liver transplantation. Combined with FKBP12 (FK506binding protein 12), the drug inhibits calcineurin leading to immunosuppression.1 Tacrolimus is absorbed in the intestine in dependent of bile, metabolized extensively in the liver via cytochrome P450, and the excreted mostly through bile with only small amounts through the urine.2 Many drugs and agents affect the tacrolimus concentration.3,4 There have also been reports that CYP3A5 genotype affects the tacrolimus concentration.5 The Chinese herb Tripterygium wilfordii Hook F, called T II, has potent anti-inflammatory properties, which led to its use to treat a variety of autoimmune diseases, such as rheumatoid arthritis, nephritis, and systemic lupus erythematosus.6 – 8 It is being studied as an immunosuppressant for organ and tissue transplantation.9,10 The principal component of T II that possesses immunosuppressive activity is the riptolide.11 A recent study has shown that triptolide cooperates with TNF-␣ (Tumor Necrosis Factor-␣) to induce apoptosis in tumor cells.12 Triptolide has also been shown to inhibit interleukin-2 expression on T cells at the
level of purine-box/nuclear factor of activated T cells and nuclear factor-B transcriptional activation and to induce T-cell apoptosis.13 Based on these effects, T II has been to be effective to prevent renal allograft rejection and increase long-term renal allograft survival among adult cadaveric renal transplant recipients.10 It can also relieve proteinuria and hematuria in nephritis. Blood concentrations of tacrolimus among receipts who received it in combination with T II were explored in this article. PATIENTS AND METHODS This prospective study included 45 patients who received T II from July 2006 to March 2007 for various reasons: 10 subjects receiving cyclosporine-based immunosuppression were excluded; eight patients showed a great change in the combined drugs, which From the Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China. Address reprint requests to Dr Leishi Li, Research Institute of Nephrology, 305 Zhongshan East Road, Nanjing, Jiangsu, China. E-mail: [email protected]
© 2008 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.08.132
Transplantation Proceedings, 40, 3679 –3682 (2008)
3679
3680
WEN, LI, CHEN ET AL
influenced tacrolimus concentrations; five patients were not followed according to a fixed protocol. Therefore, 22 patients who received primary cadaveric renal transplantations under tacrolimus were selected for this study. Some of these recipients sufferred from proteinuria after transplantation, some from hematuria, and others had a creeping creatinine above range of 0.63 to 2.86 mg/dL. The postoperative period ranged from 3 weeks to 5 years. The general characteristics of selected patients are listed in Table 1. All selected patients underwent tacrolimus concentration monitoring, and the dosages of drug were adjusted according to the concentrations. To avoid a variance of a calculated the one-time concentration, we selected three time points of stable concentration and calculated the concentration/dosage rate over 3 months before the combination of T II, as well as the average and the pre-C/D rate. After the combination with T II, we recorded tacrolimus concentrations, recording the date when the concentration increased drastically. Tacrolimus concentrations were monitored every month after 1 month. The dosage of tacrolimus was adjusted according to the concentration; three stable calculated C/D rates were assumed to be the average post-C/D rate. The difference between the post- and the pre-C/D rate was calculated as the “raising value”. Other medicines remained the same after the combination of T II in the selected patients, especially the dosages of diltiazem, antihypertensive agents, and mycophenolate mofetil (MMF), which remained the same during the observation period. Those patients who experienced changes in the listed medicine were excluded from the study. Four patients including the MZR protocol were selected as controls to avoid the effects of MMF on tacrolimus concentrations. Tacrolimus whole bood concentrations were detected using an enzyme-linked immunosorbent assay method (Diasorin Co.) before the oral drug (C0). All selected patients were tested for the CYP3A5 genotype with polymerase chain reaction followed by restriction fragment-length polymorphism analysis. The serum creatinine, proteinuria, and hematuria were also analyzed pre-and postcombination to evaluate the effects of T II. The side effects, such as liver dysfunction, leukocytopenia, and infections, were also recorded in this study.
RESULTS General Characteristics of 22 Patients
The combined immunosuppressive agents included 18 cases with FK506 ⫹ MMF ⫹ prednisone (Pred) and four cases with FK506 ⫹ mizoribine (MZR) ⫹ Pred. The primary kidney disease and other clinical characteristics of the 22 patients are listed in Table 1. The reason we added T II for these patients was to treat proteinuria (n ⫽ 12) or hemaTable 1. General Information of 22 Patients Substances
Number
Original kidney disease Chronic glomerular nephritis Hypertension Polycystic renal disease Other Ethnicity (Han) Duration of dialysis (mo) HD/CAPD
16 2 1 3 22 1–13 19/3
HD, hemodialysis; CAPD, continuous ambulatory peritoneal dialysis.
Table 2. The General and Clinical Characteristics of 22 Patients Gender (male/female)
14/8
Median age at transplant (range, y) PRA (⬎10%) Median cold ischemia time (range, h) Median warm ischemia time (range, min) CDC (%) FK506 ⫹ MMF/FK506 ⫹ MZR Causes of combination of T II Proteinuria (n) Hematuria (n) Creeping cretinine (n)
18–63 0 12–18 5–8 5–8 18/4 12/22 6/22 4/22
PRA, panel-reactive antibody; CDC, complement-dependent cytotoxicity; MMF, mycophenolate mofetil; MZR, mizoribine.
turia (n ⫽ 6) after transplantation; four cases showed a creeping creatinine (Table 2). The CYP3A5 Genotype, Concentration, Dosage, C/D Rate Pre- and Postcombination of T II
Twenty-two patients were observed for at least 6 months. Each patient’s information is listed in Table 3 according to the CYP3A5 genotype. The results showed that for each patient the tacrolimus C/D rate was increased by a different degree after the combination with T II, despite the CYP3A5 genotype, or the immunosuppressive protocol, or the duration from the operation to the combination of T II. The C/D rate increased from 1.55 to 7.23 after the combination with value most between 1.8 and 3.8. The Impact of Genotype
To compare the influence of genotype on the increase rate, we compared the subgroup containing *1 genotype (including *1/*1 and *1/*3 genotype) with the subgroup of *3/*3. No significant differences were observed between these two groups: 2.99 ⫾ 1.71 versus 2.55 ⫾ 1.07 (P ⫽ .472). FK506 ⫹ MMF group was compared with FK506 ⫹ MZR group: 2.85 ⫾ 1.51 versus 2.31 ⫾ 0.26. Although it seemed that the MMF group showed a greater increase, the difference was statistically unimportant (P ⫽ .498). However, the total number of samples in these two groups was too small to yield a statistically accurate analysis. The Effects and the Side Effects During Combination of T II
Eight of 12 patients with proteinuria were relieved after the combination according to the urine routine test. Three of four patients showed lessened hematuria after the combination with T II. Three patients with creeping creatinine showed an effective result, namely, the serum creatinine was stable or decreased. The side effects included 2/22 reversible liver dysfunctions with recovery after withdrawal of T II. After repeatedly introducing T II, the liver function of the two patients is now normal. Other possible side effects, included diarrhea, infection, leukopenia (Table 4), were probably relate to other medicines like MMF and tacrolimus, so its difficult to distinguish them.
TRIPTERYGIUM WILFORDII HOOK F
3681
Table 3. Selected Patient Information of CYP3A5 Genotype, the Intended C/D Rate, and the Immunosuppressive Agents Protocol Average C/D Rate Case
Gender/Age (y)
CYP3A5 Genetype
Duration After Operation (mo)
Pre
Post
Raising Value
Immunosuppressive Protocol
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
F/61 M/38 M/40 M/33 M/35 M/55 M/42 F/18 F/41 F/45 F/42 M/54 M/41 F/34 F/37 F/63 M/42 M/55 M/39 M/43 M/29 M/31
*1/*1 *1/*1 *1/*1 *1/*1 *1/*3 *1/*3 *1/*3 *1/*3 *1/*3 *1/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3
4 5 1/2 13 12 25 23 11 17 11 60 3 7 5 12 5 4 7 6 7 7 9
0.66 0.51 0.26 0.64 0.82 0.95 3.21 1.10 0.94 1.79 1.15 0.52 1.20 1.59 1.12 2.70 0.56 2.35 0.83 0.95 3.76 2.82
1.31 0.93 1.89 1.50 2.03 1.69 5.4 2.86 3.60 7.46 6.71 1.16 2.69 2.36 2.31 6.71 1.43 4.66 1.92 2.38 9.13 6.84
1.98 1.82 7.23 2.34 2.48 1.78 1.68 2.60 3.83 4.17 5.83 2.25 2.24 1.55 2.06 2.49 2.55 1.98 2.31 2.51 2.43 2.43
FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MZR FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MZR FK506 ⫹ MZR FK506 ⫹ MZR FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF
MMF, mycophenolate mofetil; MZR, mizoribine.
DISCUSSION
FK506, which has been used in organ transplantation for many years, is a calcineurin inhibitor.3,14 It is absorbed in the intestine and transformed in the liver, being metabolized through the cytochrome P 450 (CYP) system to be decomposed to inactive metabolites and excreted in the bile.15 Therefore, a medicine that influences the activity of cytochrome P 450 can also influence the concentrations of tacrolimus as well as of cyclosporine. For example, the calcium channel blockers used for hypertension and arrhythmia treatment like diltiazem and verapamil increase the tacrolimus and cyclosporine concentrations.16 Other drugs like the antifungal medicine fluconazole and itraconazole also increase the tacrolimus and cyclosporine concentrations.17 Therefore, the transplant physician must pay attention to the dosage and the drug concentrations to avoid rejection and calcineurin inhibitor nephrotoxicity. Table 4. The Effects and the Side Effects During This Observation After the Combination of T II Effect
Possible Side Effect
Proteinuria
8/12 relieved
Hematuria Creeping creatinine
5/6 lesson 3/4 effective (serum creatine keep stable or decrease)
Reversible liver dysfunction Diarrhea Infection
2/22 1/22 3/22
Leukopenia
2/22
Other some immunosuppressive agents such as sirolimus influence the concentrations of calcineurin inhibitors through cytochrome P 450, which may affect the immunosuppressive extent and increase the agent’s side effects.16 There are also some reports showing that other medicines influence the concentration of tacrolimus for unknown reasons. For example, proton pump inhibitors can increase tacrolimus concentrations through inhibition of CYP3A4-mediated metabolism, perhaps related to the CYP2C19 gene mutation.18,19 Some gastrointestinal prokinetic agents, like cisapride and metoclopramide, have been reported to increase tacrolimus whole blood concentrations through unclear mechanisms.20 To exclude the influence of other medicines on the tacrolimus concentrations, in these 22 cases they all remained the same during the observation period: especially the calcium channel blockers, MMF, and so on. Patients with great changes in these drugs were excluded from this study. Further evidence was obtained from three patients in this study who stopped T II with decreased tacrolimus concentrations to the previous level. Two of the three readded T II with a repeated increases, further supporting this effect. Because T II also has immunosuppressive effects and because tacrolimus combined with MMF shows powerful immunosuppression, the addition of T II, may lead immunosuppression overload, with a high risk of infection. The patient with the greatest increased rate experienced severe cytomegalovirus pneumonia 6 weeks after institution of the combination. Another patient displayed a polymavirus-
3682
associated nephropathy as proven by an allograft biopsy at 6 months after the combination. Therefore, the clinician must be careful to monitor the concentration of tacrolimus and adjusted the dosage to avoid infection. The duration from the combination of T II to the increased concentration differed from 1 week to 4 months (not listed in the table because of its imprecision). Therefore, this effect is not like the mechanism of other drugs such as antifungals and calcium channel blockers. We also observed some patients based on a cyclosporine protocol who were combined with T II, without increasing the concentration cyclospome as had happened with tacrolimus (limited data were not listed in this study). The CYP3A5 genotype also did not influence this effect. So we conjecture that this effect does not occur through the CYP pathway. Further research is needed to completely investigate T II in the human body. In conclusion, we observed that T II combined with tacrolimus in kidney transplantation recipients greatly increased tacrolimus concentrations. This pilot study showed that the effect was not related to the CYP3A5 genotype. The mechanism of this phenomenon was unclear; the metabolism of T II should be investigated in the human body, which would clarify this mechanism. The clinician should monitor the concentration of tacrolimus frequently to adjust the dosage to avoid side effects.
REFERENCES 1. Schreiber SL, Crabtree GR: The mechanism of action of cyclosporin A and FK506. Immunol Today 13:136, 1992 2. Peters DH, Fitton A, Plosker GL, et al: Tacrolimus. A review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 46:746, 1993 3. Christians U, Jacobsen W, Benet LZ, et al: Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet 41:813, 2002 4. Kuypers, DRJ: Immunosuppressive drug monitoring—what to use in clinical practice today to improve renal graft outcome. Transpl Int 18:140, 2005
WEN, LI, CHEN ET AL 5. Zhang X, Liu ZH, Zheng JM, et al: Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin Transplant 19:638, 2005 6. Tao X, Sun Y, Dong Y, et al: A prospective, controlled, double-blind, cross-over study of Tripterygium Wilfordii Hook F in the treatment of rheumatoid arthritis. Chin Med J (Engl) 102:327, 1989 7. Gu WZ, Brandwein SR: Inhibition of type II collagen induced arthritis in rats by triptolide. Int J Immunopharmacol 20:389, 1998 8. Qin WZ, Liu CH, Yang SM: Tripterygium Wilfordii Hook F in systemic lupus erythematosus. Chin Med J 94:827, 1981 9. Liao CX, Li JS, et al: Low dose cyclosporin A and Tripterygium Wilfordii inhibited porcine intestinal allograft rejection. Chin Med J (Engl) 107:669, 1994 10. Ji SM, Wang Q-W, Chen JS, et al: Clinical trial of Tripterygium Wilfordii Hook F. in human kidney transplantation in China. Transplantation Proc 38:1274, 2006 11. Gu WZ, Chen R, Brandwein S, et al: Isolation, purification, and characterization of immunosuppressive compounds from tripterygium: triptolide and tripdiolide. Int J Immunopharmacol 17:351, 1995 12. Lee KY, Chang W-T, Qiu D, et al: PG490 (Triptolide) cooperates with tumor necrosis factor-␣ to induce poptosis in tumor cells. J Biol Chem 274:134, 1999 13. Yang Y, Liu Z-H, Tolosa E, et al: Triptolide induces apoptotic death of T lymphocyte. Immunopharmacology 40:139, 1998 14. Halloran PF: Immunosuppressive drugs for kidney transplantation. N Engl J Med 351:2715, 2004 15. Venkataramanan R, Jain A, Warty VS, et al: Pharmacokinetics of FK 506 in transplant patients. Transplant Proc 23:273, 1991 16. Kuypers DRJ: Immunosuppressive drug monitoring—what to use in clinical practice today to improve renal graft outcome. Transplant Int 18:140, 2005 17. Oellerich M, Armstrong VW: The role of therapeutic drug monitoring in individualizing immunosuppressive drug therapy: recent developments. Ther Drug Monit 28:720, 2006 18. Takahashi K, Motohashi H, Yonezawa A: Lansoprazoletacrolimus interaction in Japanese transplant recipient with CYP2C19 polymorphism. Ann Pharmacother 38:791, 2004 19. Itagaki F, Homma M, Yuzawa K, et al: Effect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutations. J Pharm Pharmacol 56:1055, 2004 20. Prescott WA Jr, Callahan BL, Park JM: Tacrolimus toxicity associated with concomitant metoclopramide therapy. Pharmacotherapy 24:532, 2004
T
ACROLIMUS IS AN EFFECTIVE immunosuppressant for organ transplantation, especial in renal and liver transplantation. Combined with FKBP12 (FK506binding protein 12), the drug inhibits calcineurin leading to immunosuppression.1 Tacrolimus is absorbed in the intestine in dependent of bile, metabolized extensively in the liver via cytochrome P450, and the excreted mostly through bile with only small amounts through the urine.2 Many drugs and agents affect the tacrolimus concentration.3,4 There have also been reports that CYP3A5 genotype affects the tacrolimus concentration.5 The Chinese herb Tripterygium wilfordii Hook F, called T II, has potent anti-inflammatory properties, which led to its use to treat a variety of autoimmune diseases, such as rheumatoid arthritis, nephritis, and systemic lupus erythematosus.6 – 8 It is being studied as an immunosuppressant for organ and tissue transplantation.9,10 The principal component of T II that possesses immunosuppressive activity is the riptolide.11 A recent study has shown that triptolide cooperates with TNF-␣ (Tumor Necrosis Factor-␣) to induce apoptosis in tumor cells.12 Triptolide has also been shown to inhibit interleukin-2 expression on T cells at the
level of purine-box/nuclear factor of activated T cells and nuclear factor-B transcriptional activation and to induce T-cell apoptosis.13 Based on these effects, T II has been to be effective to prevent renal allograft rejection and increase long-term renal allograft survival among adult cadaveric renal transplant recipients.10 It can also relieve proteinuria and hematuria in nephritis. Blood concentrations of tacrolimus among receipts who received it in combination with T II were explored in this article. PATIENTS AND METHODS This prospective study included 45 patients who received T II from July 2006 to March 2007 for various reasons: 10 subjects receiving cyclosporine-based immunosuppression were excluded; eight patients showed a great change in the combined drugs, which From the Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China. Address reprint requests to Dr Leishi Li, Research Institute of Nephrology, 305 Zhongshan East Road, Nanjing, Jiangsu, China. E-mail: [email protected]
© 2008 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.08.132
Transplantation Proceedings, 40, 3679 –3682 (2008)
3679
3680
WEN, LI, CHEN ET AL
influenced tacrolimus concentrations; five patients were not followed according to a fixed protocol. Therefore, 22 patients who received primary cadaveric renal transplantations under tacrolimus were selected for this study. Some of these recipients sufferred from proteinuria after transplantation, some from hematuria, and others had a creeping creatinine above range of 0.63 to 2.86 mg/dL. The postoperative period ranged from 3 weeks to 5 years. The general characteristics of selected patients are listed in Table 1. All selected patients underwent tacrolimus concentration monitoring, and the dosages of drug were adjusted according to the concentrations. To avoid a variance of a calculated the one-time concentration, we selected three time points of stable concentration and calculated the concentration/dosage rate over 3 months before the combination of T II, as well as the average and the pre-C/D rate. After the combination with T II, we recorded tacrolimus concentrations, recording the date when the concentration increased drastically. Tacrolimus concentrations were monitored every month after 1 month. The dosage of tacrolimus was adjusted according to the concentration; three stable calculated C/D rates were assumed to be the average post-C/D rate. The difference between the post- and the pre-C/D rate was calculated as the “raising value”. Other medicines remained the same after the combination of T II in the selected patients, especially the dosages of diltiazem, antihypertensive agents, and mycophenolate mofetil (MMF), which remained the same during the observation period. Those patients who experienced changes in the listed medicine were excluded from the study. Four patients including the MZR protocol were selected as controls to avoid the effects of MMF on tacrolimus concentrations. Tacrolimus whole bood concentrations were detected using an enzyme-linked immunosorbent assay method (Diasorin Co.) before the oral drug (C0). All selected patients were tested for the CYP3A5 genotype with polymerase chain reaction followed by restriction fragment-length polymorphism analysis. The serum creatinine, proteinuria, and hematuria were also analyzed pre-and postcombination to evaluate the effects of T II. The side effects, such as liver dysfunction, leukocytopenia, and infections, were also recorded in this study.
RESULTS General Characteristics of 22 Patients
The combined immunosuppressive agents included 18 cases with FK506 ⫹ MMF ⫹ prednisone (Pred) and four cases with FK506 ⫹ mizoribine (MZR) ⫹ Pred. The primary kidney disease and other clinical characteristics of the 22 patients are listed in Table 1. The reason we added T II for these patients was to treat proteinuria (n ⫽ 12) or hemaTable 1. General Information of 22 Patients Substances
Number
Original kidney disease Chronic glomerular nephritis Hypertension Polycystic renal disease Other Ethnicity (Han) Duration of dialysis (mo) HD/CAPD
16 2 1 3 22 1–13 19/3
HD, hemodialysis; CAPD, continuous ambulatory peritoneal dialysis.
Table 2. The General and Clinical Characteristics of 22 Patients Gender (male/female)
14/8
Median age at transplant (range, y) PRA (⬎10%) Median cold ischemia time (range, h) Median warm ischemia time (range, min) CDC (%) FK506 ⫹ MMF/FK506 ⫹ MZR Causes of combination of T II Proteinuria (n) Hematuria (n) Creeping cretinine (n)
18–63 0 12–18 5–8 5–8 18/4 12/22 6/22 4/22
PRA, panel-reactive antibody; CDC, complement-dependent cytotoxicity; MMF, mycophenolate mofetil; MZR, mizoribine.
turia (n ⫽ 6) after transplantation; four cases showed a creeping creatinine (Table 2). The CYP3A5 Genotype, Concentration, Dosage, C/D Rate Pre- and Postcombination of T II
Twenty-two patients were observed for at least 6 months. Each patient’s information is listed in Table 3 according to the CYP3A5 genotype. The results showed that for each patient the tacrolimus C/D rate was increased by a different degree after the combination with T II, despite the CYP3A5 genotype, or the immunosuppressive protocol, or the duration from the operation to the combination of T II. The C/D rate increased from 1.55 to 7.23 after the combination with value most between 1.8 and 3.8. The Impact of Genotype
To compare the influence of genotype on the increase rate, we compared the subgroup containing *1 genotype (including *1/*1 and *1/*3 genotype) with the subgroup of *3/*3. No significant differences were observed between these two groups: 2.99 ⫾ 1.71 versus 2.55 ⫾ 1.07 (P ⫽ .472). FK506 ⫹ MMF group was compared with FK506 ⫹ MZR group: 2.85 ⫾ 1.51 versus 2.31 ⫾ 0.26. Although it seemed that the MMF group showed a greater increase, the difference was statistically unimportant (P ⫽ .498). However, the total number of samples in these two groups was too small to yield a statistically accurate analysis. The Effects and the Side Effects During Combination of T II
Eight of 12 patients with proteinuria were relieved after the combination according to the urine routine test. Three of four patients showed lessened hematuria after the combination with T II. Three patients with creeping creatinine showed an effective result, namely, the serum creatinine was stable or decreased. The side effects included 2/22 reversible liver dysfunctions with recovery after withdrawal of T II. After repeatedly introducing T II, the liver function of the two patients is now normal. Other possible side effects, included diarrhea, infection, leukopenia (Table 4), were probably relate to other medicines like MMF and tacrolimus, so its difficult to distinguish them.
TRIPTERYGIUM WILFORDII HOOK F
3681
Table 3. Selected Patient Information of CYP3A5 Genotype, the Intended C/D Rate, and the Immunosuppressive Agents Protocol Average C/D Rate Case
Gender/Age (y)
CYP3A5 Genetype
Duration After Operation (mo)
Pre
Post
Raising Value
Immunosuppressive Protocol
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
F/61 M/38 M/40 M/33 M/35 M/55 M/42 F/18 F/41 F/45 F/42 M/54 M/41 F/34 F/37 F/63 M/42 M/55 M/39 M/43 M/29 M/31
*1/*1 *1/*1 *1/*1 *1/*1 *1/*3 *1/*3 *1/*3 *1/*3 *1/*3 *1/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3 *3/*3
4 5 1/2 13 12 25 23 11 17 11 60 3 7 5 12 5 4 7 6 7 7 9
0.66 0.51 0.26 0.64 0.82 0.95 3.21 1.10 0.94 1.79 1.15 0.52 1.20 1.59 1.12 2.70 0.56 2.35 0.83 0.95 3.76 2.82
1.31 0.93 1.89 1.50 2.03 1.69 5.4 2.86 3.60 7.46 6.71 1.16 2.69 2.36 2.31 6.71 1.43 4.66 1.92 2.38 9.13 6.84
1.98 1.82 7.23 2.34 2.48 1.78 1.68 2.60 3.83 4.17 5.83 2.25 2.24 1.55 2.06 2.49 2.55 1.98 2.31 2.51 2.43 2.43
FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MZR FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MZR FK506 ⫹ MZR FK506 ⫹ MZR FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF FK506 ⫹ MMF
MMF, mycophenolate mofetil; MZR, mizoribine.
DISCUSSION
FK506, which has been used in organ transplantation for many years, is a calcineurin inhibitor.3,14 It is absorbed in the intestine and transformed in the liver, being metabolized through the cytochrome P 450 (CYP) system to be decomposed to inactive metabolites and excreted in the bile.15 Therefore, a medicine that influences the activity of cytochrome P 450 can also influence the concentrations of tacrolimus as well as of cyclosporine. For example, the calcium channel blockers used for hypertension and arrhythmia treatment like diltiazem and verapamil increase the tacrolimus and cyclosporine concentrations.16 Other drugs like the antifungal medicine fluconazole and itraconazole also increase the tacrolimus and cyclosporine concentrations.17 Therefore, the transplant physician must pay attention to the dosage and the drug concentrations to avoid rejection and calcineurin inhibitor nephrotoxicity. Table 4. The Effects and the Side Effects During This Observation After the Combination of T II Effect
Possible Side Effect
Proteinuria
8/12 relieved
Hematuria Creeping creatinine
5/6 lesson 3/4 effective (serum creatine keep stable or decrease)
Reversible liver dysfunction Diarrhea Infection
2/22 1/22 3/22
Leukopenia
2/22
Other some immunosuppressive agents such as sirolimus influence the concentrations of calcineurin inhibitors through cytochrome P 450, which may affect the immunosuppressive extent and increase the agent’s side effects.16 There are also some reports showing that other medicines influence the concentration of tacrolimus for unknown reasons. For example, proton pump inhibitors can increase tacrolimus concentrations through inhibition of CYP3A4-mediated metabolism, perhaps related to the CYP2C19 gene mutation.18,19 Some gastrointestinal prokinetic agents, like cisapride and metoclopramide, have been reported to increase tacrolimus whole blood concentrations through unclear mechanisms.20 To exclude the influence of other medicines on the tacrolimus concentrations, in these 22 cases they all remained the same during the observation period: especially the calcium channel blockers, MMF, and so on. Patients with great changes in these drugs were excluded from this study. Further evidence was obtained from three patients in this study who stopped T II with decreased tacrolimus concentrations to the previous level. Two of the three readded T II with a repeated increases, further supporting this effect. Because T II also has immunosuppressive effects and because tacrolimus combined with MMF shows powerful immunosuppression, the addition of T II, may lead immunosuppression overload, with a high risk of infection. The patient with the greatest increased rate experienced severe cytomegalovirus pneumonia 6 weeks after institution of the combination. Another patient displayed a polymavirus-
3682
associated nephropathy as proven by an allograft biopsy at 6 months after the combination. Therefore, the clinician must be careful to monitor the concentration of tacrolimus and adjusted the dosage to avoid infection. The duration from the combination of T II to the increased concentration differed from 1 week to 4 months (not listed in the table because of its imprecision). Therefore, this effect is not like the mechanism of other drugs such as antifungals and calcium channel blockers. We also observed some patients based on a cyclosporine protocol who were combined with T II, without increasing the concentration cyclospome as had happened with tacrolimus (limited data were not listed in this study). The CYP3A5 genotype also did not influence this effect. So we conjecture that this effect does not occur through the CYP pathway. Further research is needed to completely investigate T II in the human body. In conclusion, we observed that T II combined with tacrolimus in kidney transplantation recipients greatly increased tacrolimus concentrations. This pilot study showed that the effect was not related to the CYP3A5 genotype. The mechanism of this phenomenon was unclear; the metabolism of T II should be investigated in the human body, which would clarify this mechanism. The clinician should monitor the concentration of tacrolimus frequently to adjust the dosage to avoid side effects.
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