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I. ДИАГНОСТИКА И ЛЕЧЕНИЕ
IMPACT OF CYP3A5 GENE POLYMORPHISM ON TACROLIMUS PHARMACOKINETICS IN KIDNEY TRANSPLANT PATIENTS
Baimakhanov B.B., Chormanov A.T., Ibragimov R.P., Madadov I.K., Dabyltaeva K.S., Syrymov Zh.M.
JSC «National Scientific Center of Surgery named after A.N. Syzganov», Almaty, Kazakhstan
Abstract
Nowadays in Kazakhstan there is an active development of organ transplantation, particularly kidney transplantation. The main purpose is not only to save as much lives as possible but also improve the survival rates of graft. In this way, now we are investigating personalization and rationalization of immunosuppressive treatment. In our country as in whole world genetic factors, determinating long-term graft survival, represent a great relevancy in transplantation. According to the results of clinical trial, there is a strict association between CYP3A5 (cytochrome P450) genetic polymorphism and tacrolimus pharmacokinetics. The determination of genetic polymorphism of CYP 3A5 gives us the opportunity to predefine the changes in blood concentrations of tacrolimus, better control of immunosuppressive therapy, that will positively affect the long-term graft survival.
CYP3A5 геиетикалык полиморфизмшщ бYЙpeк реципиеиттершдеп такролимус фармакокинетикасына эсepi
Баймаханов Б.Б., Чорманов А.Т., Ибрагимов Р.П., Мададов И.К., Дабылтаева К.С., Сырымов Ж.М.
А.Н. CbßfaHOB aтындafы Улттык, гылыми хирургия ортaлыfы, Алмaты, Ka3aKCTaH
кАддтта
faeipri танда %аза%станда opran тpaнсплaнтaциясы, oныц Шид бYЙpeк тpaнсплaнтaциясы ^кынды т/pдe дамып ee жатьip. Нeгieгi максат квп^^н нayкaстapдыц вмipiн сактап калу Faha eмeс, тpaнсплaнтaттiн Jipi калу квpсeгкiшгepiн жaксapтy. Бул жoлдa б\з иммyнoсyпpeссивгi eмiнiц пepсoнaлиeaция жднe paциoнaлиea-циясын зepггeп жaтыpмыe. Бздц мeмлeкeтiмieдe жднe бук\л ДYниeдe дe тpaнсплaнтaттыц узак мepeiмдe Tipi калуын аныктайтын гeнeтикaлык фaктopлap, тpaнсплaнтoлorиядa YwceM кызы^ушылык тyдыpып жатф. ЖaсaлFaн eepттeyлepдiц ндтижeлei бoйыншa CYp3A5 (Р450 цитoxpoмы) гeнeтичeскaлык пoлимopфиeмiмeн та^лиму-стын фapмaкoкинeтикaсы apaсындa накты байланыс 6ap. CYP3A5 гeнeтичeскaлык пoлимopфиeмiн аныктау та-кpoлимyс кoнцeнтpaциясыныц кaндaFы вeгepiстepiн алдын ала б\лу, иммyнoсyпpeссивтi eмдi жаксы^ак бакылау мYмкiншiлiriн тyдыpaды жднe бул тpaнсплaнтaттыц узак мepeiмдe Tipi калу ^poernmep\н жaксapтaды.
МРНТИ 76.31.29
ABOUT THE ÄUTHORS B.B. Baimakhanov - professor, transplant-surgeon, chairman of Board of JSC«National Scientific Center of Surgery named after A.N. Syzganov» ([email protected], 87017223381). A.T. Chormanov - can of med sci., transplant-surgeon, cheaf physician of JSC National Scientific Center of Surgery named after A.N. Syzganov ([email protected],
R.P. Ibragimov - urologist, transplant-surgeon, head of kidney transplantation, urology and nephrology department, scientific manager. ([email protected] 87017472070) I.K. Madadov - urologist, kidney transplantation, urology and nephrology department ([email protected] 87478397110) K.S. Dabyltaeva - nephrologist, kidney transplantation, urology and nephrology department. ([email protected] 87027651566) Zh.M. Syrymov - urologist, kidney transplantation, urology and nephrology department. ([email protected] 87072727002)
Keywords
tacrolimus, kidney transplantation, genetic polymorphism, immuno-suppressive.
АВТОРЛАР ТУРАЛЫ Б.Б. Бтймтхтнов - пpoфeссop, rpa^o-^ла^-^onorдэp\гep\, «Улттык Гылыми X^pyp-гия opтaлыFы» А^-нын бас^ма твapaFaсы (info@baimakhanov. kz,, 87017223381). А. Т. Чормтнов - ждицина Fылымдapынын кандидаты, rpa^o-^ла^-^onor дэp\гep\, «Улттык пылыми Xnpyprw opтaлыFы» А%-ныц бас дэp\гep\ ([email protected], 87019899900). Р. П. Ибрагимов - yponor^Tpa^c^an^o-mrдэp\гep\, 6YЙpeк тpaнсплaнтaциясы, ypomrm rn4e нeфpoлoгия 6вл\мшeс\н\ц жeтeкш\с\, Fылыми жeтeкш\ (rava747@maií. ru 87017472070)
И.К. Мтдтдов - ypomrдэp\гep\, 6YЙpeк тpaнсплaнтaциясы, ypoлoгия жэнe 4e-фpoлoгия 6вл\мшeс\ ([email protected] 87478397110)
К- С. Дабылтаева - нeфpoлoгдэp\гep\, 6YЙpeк тpaнсплaнтaциясы, yponorm жэнe нeфpoлoгия 6вл\мшeс\ (d_kuralay_s@mail. ru 87027651566)
Ж.М. Сырымов - yponor дэp\гep\, 6YЙpeк тpaнсплaнтaциясы, ypomrm жэнe нeфpoлoгия 6вл\мшeс\ (syrymov89@mail. ru 87072727002)
Туйш сездер
тaкpелимyol тpaнoплaнтaцияl 6YЙpeк, reнeтичeoкaлык пели-меpфиeмl иммyнеoyпpeooия.
Влияние генетического полиморфизма CYP3A5 на фармакокинетику такролимуса у реципиентов почки
Баймаханов Б.Б., Чорманов А.Т., Ибрагимов Р.П., Мададов И.К., Дабылтаева К.С., Сырымов Ж.М.
Национальный научный центр хирургии имени А.Н. Сызганова, Алматы, Казахстан
Аннотация
На сегодняшний день в Казахстане идёт активное развитие трансплантации органов, в частности, пересадка почки. Главной целью является не только спасти как можно больше жизней, но и улучшить показатели выживаемости трансплантата. В этом направлении сегодня мы исследуем персонализацию и рационализацию иммуносу-прессивно терапии. В нашей стране, как и во всем мире генетические факторы, детерминирующие выживаемость трансплантата в отдаленном периоде, предсталяет собой огромный интерес в трансплантологии. Согласно проведенным результатам имеется четкая связь между генетическим полиморфизмом CYP3A5 (цитохром Р450) с фармакокинетикой такролимуса. Определение генетического полиморфизмам CYP3A5 позволит предопределить изменения концентрации такролимуса в крови, лучше контролировать иммуносупрессивную терапию, что положительно скажется на выживаемости трансплантата в отдаленном периоде.
ОБ АВТОРАХ
Б.Б. Бтймтхтнов - пpефeooеp, тpaнo-плaнтелег, пpeдoeдaтeль пpaвлeния АО «Нaциенaльнеге нayчнеге цeнтpa xиpypгии им. А.Н. Сызгaнoвa» (info@baimakhanov. kz, 87017223381).
А.Т.Чормтнов - к.м.н., главный вpaч, АО Нaциенaльнеге нayчнеге цeнтpa xиpypгии им. А.Н. Сызгaнoвa ([email protected],
Р. П. Ибртгимов - уpoлoг-тpaнcплaн-телег, eaвeдyющий етдeлeниeм тpaнo-плантации печeк, ypелегии и нeфpелегии, pyкеведитeль иooлeдевaния (rava747@ maii.ru 87017472070)
И.К. Мтдтдов - уpoлoг, oтделение тpaнc-плантации печeк, ypелегии и нeфpелегии, младший научный oетpyдник (dominic89@ maii.ru 87478397110)
К.С. Дабылтаева - нeфpелег, етдeлeниe тpaнoплaнтaции печeк, ypелегии и нeфpе-лoгии, ([email protected] 87027651566) Ж.М. Сырымов - уpoлoг, oтделение тpaнoплaнтaции печeк, ypелегии и нeфpе-лoгии ([email protected] 87072727002)
Ключевые слова
тaкpoлимyс, тpaнсплaнтaция, гeнeтичeский пoлимopфизм, иммyнoсyпpeссия.
BULLETIN OF SURGERY IN KAZAKHSTAN № 1-2019
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Fig. 1.
Changes of tacrolimus concentration with CYP 3A5 genetic polymorphism
Introduction
Nowadays kidney transplantation is the most preferable treatment option of terminal chronic kidney disease. The main advantage of kidney transplantation is that graft totally replaces the function of diseased kidney. Improvement of the quality of life of patients and return to their daily activities is another great advantage of this option.
With the improvement of donor selection, surgical technique and rational immunosuppressive treatment rates of short-term graft survival great increased. 1 - year graft survival from deceased donor is 95% whereas from living related donor is 98%. In Kazakhstan 1-year graft survival from living related donor is 91%. Despite these high indicators of 1-year graft survival, 5-year graft survival rates remain to be low. For example, in USA 5-year graft survival from decease donor is up to 80%, whereas from living donor is form 82 to 90 %, respectively. Thus, despite the improvement of short-term graft survival rates, long-term graft survival rates remain to be low [1].
So what lies under the graft loss in long-term period? It is thought to be that the main reason of graft loss in long-term period is so called graft nephropathy. The reasons of graft nephropathy are immunologic factors and, probably, genetic factors.
Recently there are many transplant centers where genetic factors and their influence of kidney graft function are investigated. In this way investigation of CYP3A5 genetic polymorphism, as a regulatory factor of tacrolimus pharmacokinetics is being more relevant.
Material and methods
We conducted a clinical trial, where we include 80 kidney recipients. Of them, 47 were male and 33 female patients. Mean age of patients was 43y4.1 years. All patients had been taking tacrolimus 0.1 mg/kg initially. Dose adjustment was by 1.0 mg a day up to target concentration (10-12 ng/
ml). All patients were studied for CYP3A5 genetic polymorphism.
Results
According to the received results 77 % of patients were CYP3A5*3 *3 homozygotes and the rest 33% were CYP3A5*1 *3 heterozygotes. Thus, first were classified as 1 group and the last as 2 group. At dose of 0.1 mg/kg in patients of both groups showed similar increase of tacrolimus level initially, but starting from the 2 week there was seen rapid increase of tacrolimus level in patients from the 1 group and dose adjustment was problematic due unpredictable course of concentration (Tab. 1). In patients from the 2 group tacrolimus concentration increased gradually without peaks and approximately at 2 weeks in postoperative period target concentration was reached. In contrast in patients form 1 group, at 2 weeks postoperatively we continued dose adjustment due to unpredictable rises and rapid falls of tacrolimus concentration.
Discussion
Fan B et al. studied pharmacokinetics of tacrolimus in patients taking prograf and advagraf [2]. 106 kidney transplant patients were included in this study. 61 of them had been taking prograf and 45 - advagraf. In 40% of patients there was low expression CYP3A5. In these patients target concentration of tacrolimus was reached at 21 day in advagraf group and 7 days in prograf group. 1-year graft survival was same in both groups. Infection was seen more frequently in patients taking advagraf.
Cheng et al. [3] studied 35 kidney recipients. Patients were divided in to 3 groups. First group were patients homozygote carriers of CYP3A5 (*1*1), the second group homozygote carriers of CYP3A5 (*3*3) and 3 group of patients heterozygotes of CYP3A5 (*1*3). Dose adjustment was performed after 7
20
15
10
■CYP3A5*3*3 ■CYP3A5*1*3
О
-1-1-1-1-1
CI C2 C3 C4 C5
6
ВЕСТНИК ХИРУРГИИ КАЗАХСТАНА № 1-2019
days, 1, 6 and 12 months postoperatively. Patients from the 1 group need high doses of tacrolimus in order to reach target concentration. There was high risk of graft rejection reaction in 1 group.
Similar results were received in clinical trial conducted by Quteineh L et al. [4] 136 kidney recipients were studied. As was in previous investigation patients with CYP3A5*1*1 genotype need higher doses of tacrolimus to reach the target concentration. Interestingly the situation remained the same for subsequent 6 and 12 months. CYP3A5 genetic polymorphism was not associated with tacrolimus nephrotoxicity but influenced the dose adjustment. Authors suggest preoperative evaluation of CYP3A5 genetic polymorphism, especially CYP3A5*1 carries.
Zhang X et al. [5] studied 118 kidney recipients. In CYP3A5*1*1 and *1*3 carriers tacrolimus concentration remained low even after dose adjustment in contrast to CYP3A5*3*3 carriers. For instance, half of patients with CYP3A5*1 after 7
References
1. Glowacki F, Lionet A, Buob Det al. «CYP3A5 and ABCB1 polymorphisms in donor and recipient: impact on Tacrolimus dose requirements and clinical outcome after renal transplantation». Nephrology Dialysis Transplantation. 2011. P. 3046-3050.
2. Fan B, Qiu K, Jiang Y, Hu X, Yin H. «Prograf produces more benefits for CYP3A5 low expression patients in early stage after kidney transplantation». Biomed Pharmacotherapy. 2017. P. 738-744.
3. Cheng Y, Li H, Meng Y, Liu H «Effect of CYP3A5 polymorphism on the pharmacokinetics of tacrolimus and acute rejection in renal transplant recipients: experience at a single centre». International Journal Clinical Practice Supply. 2015 May. P. 16-22.
4. Quteineh L, Verstuyft C, Furlan V et al. «Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft
days from initiation of immunosuppression tacrlimus was less than 5 ng/ml, whereas in CYP3A5*3 carriers tacrolimus concentration was more than 20 ng/ml. Thus this genetic factor is one of most important regulators of rational immunosuppressive treatment.
Conclusion
It is obvious from received results, that genetic polymorphism of CYP3A5 influences tacrolimus blood concentrations, that appears to be key factor in immunesupression [6]. Even in rational choice of dose of immunosuppressive agent, genetic factor must be considered as well. In order to improve long-term graft survival rates it is important to maintain therapeutic concentration of tacrolimus in blood. In this way in might important to determine the CYP3A5 genetic polymorphism preoperatively [7], as one of approved genetic determinants of graft survival. It is also important for the correct selection of initial dose.
recipients» Basic Clinical Pharmacologic Toxicology. 2008. P 546-552.
5. Shi Y, Li Y, Tang J, Zhang J et al. «Influence of CYP3A4, CYP3A5 and MDR-1 polymorphisms on tacrolimus pharmacokinetics and early renal dysfunction in liver transplant recipients». Gene. 2013 . P. 226-231.
6. Provenzani A, Notarbartolo M, Labbozzetta M et al. «Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients». International Journal of Molecular Medicine. 2011/ P.1093-1102.
7. Zhang X, Liu ZH, Zheng JM, Chen ZH, Tang Z, Chen JS, Li LS. « Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation». Clinical Transplantation. 2005, P. 638-643.
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