Effect Of CYP3A5 Genotype Research Articles

Effects of CYP3A5 Genotypes on Thrombocytopenia in Liver Transplantation Patients Treated with Tacrolimus.

Thrombocytopenia is a complication after liver transplantation. This study's aims were to evaluate the role of CYP3A5 genotypes on tacrolimus-induced thrombocytopenia after orthotopic liver transplantation. In this retrospective case-control study, data from 100 patients who underwent deceased-donor liver transplantation (DDLT) were divided into CYP3A5*3 genotype (donor/recipient) tacrolimus fast- (A*/A*, n = 22), intermediate- (A*/GG, n = 20; GG/A*, n = 31) and slow-metabolizer (GG/GG, n = 27) groups. Platelet count changes and prognosis for 180 days after surgery were compared. Platelet counts declined significantly after DDLT, especially on postoperative day (POD) 3, and continued at low levels for a week thereafter in all groups. In the GG/GG group, platelet counts on POD3 (50.29 ± 5.44 × 109/L) were the lowest among the groups (A*/A*, 71.00 ± 6.22 × 109/L; A*/GG, 57.95 ± 6.21 × 109/L; GG/A*, 75.90 ± 5.56 × 109/L) (p = 0.006). Compared with the A*/A* genotype, tacrolimus nadir levels were significantly higher in GG/GG genotype patients, who also exhibited a higher incidence of hemorrhage (22.2%, p = 0.011). A combination of a nadir blood concentration of tacrolimus ≥ 4.74 ng/mL and spleen size ≥ 165.5 mm was a risk factor for increased thrombocytopenia after DDLT on POD3, with an AUC of 0.735 (sensitivity, 77.2%; specificity, 41.7%). A high blood concentration of tacrolimus after the early stage of DDLT is a major risk factor for hemorrhage. For the CYP3A5 genotype (GG/GG), controlling the blood concentration of tacrolimus below the target concentration until POD3 can avoid thrombocytopenia-related complications.

Effect of CYP3A5 genotypes on serum carbamazepine concentrations at steady-state in Vietnamese epileptic patients

Effect of CYP3A5 genotypes on serum carbamazepine concentrations at steady-state in Vietnamese epileptic patients

P446. Effects of CYP3A5 genotype on efficacy and safety of tacrolimus in refractory ulcerative colitis: experience from a tertiary referral centre

P446. Effects of CYP3A5 genotype on efficacy and safety of tacrolimus in refractory ulcerative colitis: experience from a tertiary referral centre

Effects of CYP3A5 Genotype on Efficacy and Safety of Tacrolimus in Refractory Ulcerative Colitis: An Experience From a Tertiary Referral Center in Japan

Introduction: A calcineurin inhibitor, tacrolimus (TAC), is widely used as an induction therapy for steroid-refractory ulcerative colitis (UC) patients in Japan. Although its efficacy in inducing remission is comparable with other treatment options such as anti-tumor necrosis factor antibodies, its longterm efficacy is not well studied. Its long-term use may lead to an increased incidence of side effects including renal dysfunction. Furthermore, its efficacy as well as toxicity depends on the blood trough level, which requires the frequent monitoring of blood concentration. Both patients and physicians may want to avoid using Tac due to these factors. Here we retrospectively tried to examine the association of genotyping the single nucleotide polymorphism of CYP3A5, the metabolizing enzyme of tacrolimus, with the dosing, long-term efficacy, and incidence of renal dysfunction by TAC for UC in our institution. Methods: Medical records of 21 patients with UC who were treated with TAC for more than 2 weeks were retrospectively reviewed (M:F=13:8). Mean duration of TAC treatment was 308 +/- 284 days. CYP3A5*3(A6986G) was genotyped using the TaqMan real-time polymerase chain reaction assays. 1) Dose of TAC required to reach the therapeutic level (10 ug/ml) 2) incidence of renal dysfunction 3) short- and long-term clinical efficacy outcome was examined in combination of CYP3A5 genotypes. Renal dysfunction was defined by the 25% increase of serum creatinine (Cr). All analyses were conducted under the approval of institutional review board of Kitasato Institute Hospital. Results: CYP3A5*3 genotypes were *3/*3 in 10, *1/*3 in 9, and *1/*1 in 2 patients. 1) The dose required to reach the therapeutic trough level was significantly lower in non-expressor (*3/*3) compared with expressor (*1/*3 and *1/*1). 2) 13 out of 21patients (62%) suffered from renal dysfunction, which was not associated with CYP3A5 genotype but with the trough concentration during the treatment. Most cases recovered after discontinuing or switching Tac to thiopurines. 3) Short- and long-term efficacy outcome was not affected by the genotype. Conclusion: CYP3A5 genotype seemed useful for determining the initial dose of TAC, but was not associated with the incidence of side effects and efficacy. There was a significant proportion of patients who were maintained for longer than 3 months by TAC in combination with thiopurines, however, the incidence of gradual decrease of renal function was frequent.

Effects of CYP3A5 genotypes, ABCB1 C3435T and G2677T/A polymorphism on pharmacokinetics of Tacrolimus in Chinese adult liver transplant patients

1. The purpose of this study was to establish a population pharmacokinetic (PK) model of tacrolimus and evaluate the influence of clinical covariates, including the genetic polymorphisms of the cytochrome P450 3A5 gene (CYP3A5) and gene-encoding P-glycoprotein (ABCB1), on the PK parameters in Chinese adult liver transplant recipients.2. Details of drug dose, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data early after liver transplant. Tacrolimus PKs was studied by a non-linear mixed-effect modeling (NONMEM) method. CYP3A5 genotypes, ABCB1 C3435T and G2677T/A polymorphism and a number of clinical covariates were tested for their influence on TAC PKs.3. A one-compartment model with first-order absorption and elimination adequately described the data. Apparent clearance (CL/F) and apparent volumes of distribution (V/F) in final population model were 17.6 L/h and 225 L, respectively. The absorption rate constant (Ka) was fixed at 4.48 h−1. The inter-individual variability in CL/F and V/F was 53.9 and 68%, respectively. In the final model, CYP3A5 genotype, post-operative day, alanine aminotransferase, total bilirubin, hematocrit and blood urea nitrogen were found to significantly influence the CL/F, whereas POD and HB influence V/F.4. Population PK analysis of tacrolimus in Chinese adult liver transplant patients resulted in identification of the CYP3A5 genotype, POD, BUN, ALP, HCT, TBIL and HB as significant covariates on the PK parameters of tacrolimus.

Effect of CYP3A5 Genotypes on the Pharmacokinetics of Carbamazepine when used as Monotherapy or Co-Administered with Phenytoin, Phenobarbital or Valproic Acid in Thai Patients

To determine the effects of CYP3A5 polymorphisms on carbamazepine (CBZ) pharmacokinetic parameters when CBZ is used either as monotherapy or co-administered with phenytoin (PHT), phenobarbital (PB) or valproic acid (VPA). Retrospective data were collected from an electronic database and medical records. Blood samples were obtained and drug concentrations analyzed as a part of routine therapeutic drug monitoring (TDM). Screening for wild-type CYP3A5*1 and CYP3A5*3 single nucleotide polymorphism (rs776746) by allelic discrimination assay using real-time polymerase chain reaction technique (real-time PCR) was performed. Pharmacokinetic parameters of CBZ; clearance and dose-adjusted CBZ levels in patients with different genotypes were calculated and compared. Of the 70 patients assessed, 8 (11%) patients were homozygous CYP3A5*1/*1, 28 (40%) patients were heterozygous CYP3A5*1/*3, and 34 (49%) patients were homozygous CYP3A5*3/*3. The CBZ clearance and dose-adjusted CBZ levels did not significantly differ between patients with CYP3A5*1 and CYP3A5*3 alleles when CBZ was used as monotherapy. For patients who used CBZ in combination with an enzyme-inducing antiepileptic drug (AED: PHT or PB), individuals carrying the CYP3A5*1 allele (CYP3A5 expressers) showed a trend of having higher CBZ clearance and lower dose-adjusted CBZ level as compared to individuals carrying the CYP3A5*3 allele, even though no statistical significance was recorded. Nevertheless, it was observed that AEDs significantly increased CBZ clearance only in patients carrying the active CYP3A5*1 allele. When CBZ was used in combination with enzyme-inducing AED, CYP3A5 expressers yielded a trend toward greater susceptibility to change in CBZ clearance and showed lower dose-adjusted CBZ levels compared to CYP3A5 non-expressers. The dosage regimen should be adjusted accordingly to gain a better clinical outcome.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Effect of CYP3A5 Genotype on Renal Allograft Recipients Treated With Tacrolimus

Objective Tacrolimus concentrations are associated with CYP3A5 genotype. The purpose of this study was to evaluate the outcomes and drug concentrations/doses among a posttransplant population with various CYP3A5 genotypes within 12 months. Methods Sixty seven kidney recipients receiving immunosuppression with tacrolimus + mycophenolate mofetil + prednisolone were grouped according to their CYP3A5 genotypes (*1/*1; *1/*3; *3/*3). The initial dose of tacrolimus (0.15 mg/kg/d) was adjusted according to achieve a target therapeutic window. All patients underwent a protocol biopsy at 1 month posttransplantation. We assayed serum creatinine and tacrolimus blood trough concentrations to calculate the concentration per dosage during follow-up. We also investigated the incidence of acute rejection episodes and the nephrotoxicity of tacrolimus according to the renal biopsy. Results There was no significant difference among serum creatinine concentrations. Tracrolimus blood concentrations showed a significant difference at day 7 and 1 month with no significant difference at 3, 6, or 12 months among the three groups. The CYP3A5*3/*3 group showed the largest concentration per dosage (C/D) and CYP3A5*1/*1, the smallest C/D. There was a significant difference among the three groups. The occurrence of an acute rejection episode within 3 months showed a significant difference among the three groups but not from 3 to 12 months after transplantation. Nephrotoxicity was greatest among the CYP3A5*3/*3 group. Conclusion CYP3A5 influenced the blood concentrations of tacrolimus. Our study suggested to choose the initial dosage according to the CYP3A5 genotype to obtain a better outcome and reduce the incidences of acute rejection episodes and nephrotoxicity.

Effect of CYP3A5 genotype on ketoconazole induced QT prolongation

Background/Aim Ketoconazole (Keto) is used extensively as a test inhibitor of cytochrome P450 3A-mediated metabolism in clinical drug interaction studies with drugs that might prolong the QT interval. Prior studies in healthy volunteers suggested that Keto itself, (400mg per day by mouth) contributes to QTc prolongation but inter-individual variability was substantial. We tested the hypothesis that inter-individual difference in prolongation of QTc by Keto are associated with CYP3A5 genotype. Methods 15 healthy volunteers (12 males, 29± 9 yrs) participated in a three phase randomized, crossover study. The subjects were treated with either 200mg QD or 400mg QD of Keto for 6 days. QT interval was measured before, and after treatment using a digitizing pad in three consecutive beats in leads II and V5. The measured QT was corrected based on a linear multiple regression model with log-transformed data (QT and RR). CYP3A5 genotype was done by allele specific real time PCR. Results (see Table 1 and Table 2). Conclusions 200mg of ketoconazole induced prolongation in QTc (delta QTc= 17.2 msec, p<0.0032) as did the 400mg dosage regimen (delta QTc= 16.8 msec, p<0.0065). Subjects who carried two CYP3A5*3 alleles had greater QTc than those with at least one*1 allele (p<0.0001). The extent of QTc prolongation with Keto was independent of CYP3A5 genotype. Clinical Pharmacology & Therapeutics (2005) 77, P5–P5; doi: 10.1016/j.clpt.2004.11.021 Table 1. Effect of Keto on QTc prolongation QTc msec (Mean ± SE) Phase 1 (baseline) 382.2 ± 4.2 Phase 2 399.4 ± 4.8 Phase 3 399.0 ± 4.4 Table 2. Effect of CYP3A5 genotype on Keto induced QTc prolongation CYP3A5 genotype Baseline QTc msec (mean ± SE) QTc msec (mean ± SE) at the end of Keto therapy *1/*1 (n = 3) 369.2 ± 5.3 386.1 ± 5.4 *1/*3 (n = 4) 366.4 ± 5.1 383.4 ± 5.0 *3/*3 (n = 8) 394.2 ± 4.1 411.2 ± 3.7

Dose dependent inhibition of midazolam elimination by ketoconazole: Effect of CYP3A5 genotype

Aims Ketoconazole (K), a potent inhibitor and substrate of CYP3A enzymes, is commonly used to determine the worst-case drug interaction for CYP3A substrates. The effect of K dose and CYP3A5 genotype on in vivo CYP3A activity was assessed using the probe drug, midazolam (M). Methods 15 healthy volunteers (12 male), weighing (mean±SD) 76±12kg, completed a 3-phase, randomized, crossover study. Intravenous (IV, 0.05mg/kg over 30 minutes) and oral (4mg) M were administered on separate days before and during 7 days of dosing with K 200 or 400mg (K 1hr prior to IV M on day 6 and oral M on day 7). Serum samples were assayed for M and K by HPLC-MS. CYP3A5 genotype was obtained by allele-specific real-time PCR. Results The baseline AUCs after IV and oral M were 149±29 and 45±16μg×L/hr. The baseline oral bioavailability, systemic and oral clearance of M were 0.27±0.06, 26±6L/hr and 99±32L/hr, respectively. The average steady state concentration of K after 200mg and 400mg dosing was 1.3±0.5 and 3.9±1.4 mg/L, respectively. The fold increase in IV & oral M AUC was significantly greater (P≤0.02) after 400mg K (4.2±0.6 & 15±4, respectively) compared to 200mg K (3.4±0.7 & 11±4, respectively) daily. CYP3A5 genotype (*1/*1, *1/*3; n=7 vs. *3/*3; n=8) did not significantly alter the extent of inhibition observed after K dosing (P>0.05). Conclusions The extent of CYP3A inhibition by K is dose dependent with significantly greater effect by 400mg compared to 200mg K dosing. Grant support FDT-001756 from FDA and M01-RR00750 from NIH. Clinical Pharmacology & Therapeutics (2005) 77, P35–P35; doi: 10.1016/j.clpt.2004.12.025