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Open access

Dragana Dragas Milovanovic, Ivan Radosavljevic, Marija Radovanovic, Jasmina R. Milovanovic, Slobodan Obradovic, Slobodan Jankovic, Dragan Milovanovic and Natasa Djordjevic


Carbamazepine exhibits significant inter-individual variability in its efficacy and safety, which leads to unpredictable therapy outcomes for the majority of patients. Although its complex biotransformation depends on CYP3A5 activity, evidence of association between carbamazepine treatment outcomes and CYP3A5 functional variations remains inconclusive. The aim of the present study was to investigate the distribution of two of the functionally important CYP3A5 variants *2 and *3 as well as their effects on carbamazepine dose requirements, plasma concentrations and clearance in a Serbian population. The study involved 40 paediatric epileptic patients on steady-state carbamazepine treatment. Genotyping was conducted using the PCR-RFLP method, and carbamazepine plasma concentrations were determined using the HPLC method. CYP3A5*2 and *3 polymorphisms were found at frequencies of 0.0% and 97.5%, respectively, which corresponds well to previously published data for Caucasians. No differences in CYP3A5*3 allele frequencies were detected among epileptic patients in comparison to healthy volunteers within similar ethnic populations (p>0.08), indicating that CYP3A5 polymorphism does not represent a risk factor for epilepsy development. There was an observed tendency towards lower dosage requirements (mean±SD: 15.06±4.45 mg/kg vs. 18.74±5.55 mg/kg; p=0.26), higher plasma concentrations (mean±SD: 0.45±0.13 mg/kg vs. 0.38±0.03 mg/kg; p=0.47) and lower clearance (mean±SD: 0.14±0.05 mg/kg vs. 0.15±0.01 mg/kg; p=0.79) of carbamazepine in homozygous carriers of CYP3A5*3/*3 compared to heterozygous CYP3A5*1A/*3 Serbians. Because these genotype groups did not differ significantly in terms of their carbamazepine pharmacokinetics parameters, the proposed effects of CYP3A5*3 on carbamazepine metabolism could not be confirmed.

Open access

Nikola Z. Stefanović, Tatjana P. Cvetković, Radmila M. Veličković-Radovanović, Tatjana M. Jevtović-Stoimenov, Predrag M. Vlahović, Ivana R. Stojanović and Dušica D. Pavlović


Background: The primary goal of this study was to evaluate the influence of cytochrome P450 (CYP) 3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms on tacrolimus (TAC) dosage regimen and exposure. Second, we evaluated the influence of TAC dosage regimen and the tested polymorphisms on renal oxidative injury, as well as the urinary activities of tubular ectoenzymes in a long-term period after transplantation. Also, we aimed to determine the association between renal oxidative stress and tubular damage markers in the renal transplant patients.

Methods: The study included 72 patients who were on TAC based immunosuppression. Allele-specific PCR was used for polymorphism determination. We measured the urinary thiobarbituric acid reactive substances (TBARS) and reactive carbonyl derivates (RCD) in order to evaluate oxidative injury, as well as the urinary activities of ectoenzymes (N-acetyl-β-D-glucosaminidase, aminopeptidase N and dipeptidyl peptidase IV) to evaluate tubular damage.

Results: The carriers of CYP 3A5*1 allele required statistically higher daily doses of TAC than CYP *3/*3 carriers, as well as the carriers of C allele of ABCB1 gene compared to those with TT genotype. Also, there were no differences in TBARS, RCD and the activities of ectoenzymes between the patients’ genotypes. Our results showed significant correlations between urinary TBARS and RCD and the ectoenzymes’ activities.

Conclusions: Our findings suggest that CYP 3A5 and ABCB1 3435 polymorphism may affect TAC daily doses, but not the drug’s tubular toxicity. Furthermore, tubular damage may be associated with increased renal oxidative stress.

Open access

Kreetachon Veerakikosol, Pajaree Chariyavilaskul, Natavudh Townamchai and Supeecha Wittayalertpanya



Cytochrome P450 (CYP) 3A5 is a major isoform metabolizing tacrolimus. Individual variation in the metabolism may result from CYP3A5 single nucleotide polymorphisms (SNPs). CYP3A5*3 polymorphism is strongly associated with tacrolimus pharmacokinetic variations in 65%–85% of Asian populations. A minor polymorphism related to requirement for tacrolimus is the POR*28 mutation, which increases in vivo CYP3A activity for tacrolimus. These two SNPs might affect individual maintenance dosages of tacrolimus.


To determine the association of CYP3A5*3 and POR*28 SNPs with maintenance dosage requirements for tacrolimus in Thai recipients of kidney transplants.


We enrolled 150 Thai recipients of kidney transplants. Clinical laboratory data were recorded 3 months after first administration of tacrolimus. Two SNPs; rs776746 A > G (CYP3A5*3 allele) and rs1057868 C > T (POR*28 allele) were assessed. All 300 genotypes were analyzed by real-time polymerase chain reactions.


Recipients were classified into 9 groups according to possible matching genotypes. The mean dosage required for the maintenance phase was significantly higher in the CYP3A5*1 allele or CYP3A5 expressers (groups 1-6, 0.163, 0.167, 0.141, 0.128, 0.131, and 0.174 mg/kg/day, respectively) than those not expressing CYP3A5*3/*3 or CYP3A5 (groups 7-9, 0.081, 0.073, and 0.069 mg/kg/day, respectively, P < 0.05). When the mean dosage was compared under POR*28 one or two alleles in CYP3A5 expressers, P was significantly smaller than in CYP3A5 expressers with POR*1/*1.


CYP3A5 polymorphism is key to determining tacrolimus dosage requirements during the maintenance phase in kidney transplant recipients and POR*28 may contribute to the interindividual variability