Risk of Tacrolimus Toxicity in CYP3A5 Nonexpressors Treated With Intravenous Nicardipine After Kidney Transplantation

Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Transplantation (Impact Factor: 3.83). 04/2012; 93(8):806-12. DOI: 10.1097/TP.0b013e318247a6c7
Source: PubMed


Tacrolimus is commonly prescribed for immunosuppression, yet it can cause acute and chronic kidney injury. Continuous intravenous nicardipine (CIVN), prescribed for posttransplant hypertension, inhibits tacrolimus metabolism by cytochrome P450 (CYP) 3A4 and could lead to tacrolimus overexposure in patients genetically lacking the alternative pathway for tacrolimus metabolism, CYP3A5.
We compared maximum 12-hr tacrolimus trough levels (MaxC0) and dose-adjusted MaxC0 in 12 cases treated with CIVN immediately after kidney transplantation with 26 controls (no CIVN). CYP3A5 genotype was determined for all cases.
Eight cases not expressing CYP3A5 (CYP3A5*3/*3) had higher median MaxC0 (24.3 ng/mL) than four cases expressing CYP3A5 (CYP3A5*1/*1; 13.9 ng/mL, P=0.028) and controls (14.6 ng/mL, P=0.003). Compared with the other two groups combined, CYP3A5*3/*3 cases had higher median dose-adjusted MaxC0 (330 vs. 175, P=0.012), less time to MaxC0 (42 vs. 72 hr, P<0.001), and more scheduled tacrolimus doses held per patient (1.75 vs. 0.4, P=0.007). Six of eight (75%) CYP3A5*3/*3 cases had potentially toxic MaxC0 (>20 ng/mL) compared with none of four CYP3A5*1/*1 cases and 3 of 26 (11.5%) controls (P<0.001, CYP3A5*3/*3 cases vs. all others).
CYP3A5 nonexpressors simultaneously treated with tacrolimus and CIVN may be at increased risk for tacrolimus toxicity.

15 Reads
  • Source
    • "Discovering new SNPs which can determine the onset of ADR or affect treatment efficacy will allow for the use of personalized therapeutic regimens that are free from side effects. For example, immunosuppressant drugs such as Tacrolimus (currently used in the management of solid organ transplant recipients) are also extensively metabolized by CYP3A isoenzymes [22-25]. In this context, our study may also be useful for further analyzing SNPs with significant influence on the metabolism and/or inter-individual pharmacokinetic variability of Tacrolimus in tranplants. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Drug metabolism via the cytochrome P450 (CYP450) system has emerged as an important determinant in the occurrence of several drug interactions (adverse drug reactions, reduced pharmacological effect, drug toxicities). In particular, CYP3A4 and CYP3A5 (interacting with more than 60% of licensed drugs) exhibit the most individual variations of gene expression, mostly caused by single nucleotide polymorphisms (SNPs) within the regulatory region of the CYP3A4 and CYP3A5 genes which might affect the level of enzyme production.In this study, we sought to improve the performance of sensitive screening for CYP3A polymorphism detection in twenty HIV-1 infected patients undergoing lopinavir/ritonavir (LPV/r) monotherapy. Methods: The study was performed by an effective, easy and inexpensive home-made Polymerase Chain Reaction Direct Sequencing approach for analyzing CYP3A4 and CYP3A5 genes which can detect both reported and unreported genetic variants potentially associated with altered or decreased functions of CYP3A4 and CYP3A5 proteins. Proportions and tests of association were used. Results: Among the genetic variants considered, CYP3A4*1B (expression of altered function) was only found in 3 patients (15%) and CYP3A5*3 (expression of splicing defect) in 3 other patients (15%). CYP3A5*3 did not appear to be associated with decreased efficacy of LPV/r in any patient, since none of the patients carrying this variant showed virological rebound during LPV/r treatment or low levels of TDM. In contrast, low-level virological rebound was observed in one patient and a low TDM level was found in another; both were carrying CYP3A4*1B. Conclusions: Our method exhibited an overall efficiency of 100% (DNA amplification and sequencing in our group of patients). This may contribute to producing innovative results for better understanding the inter-genotypic variability in gene coding for CYP3A, and investigating SNPs as biological markers of individual response to drugs requiring metabolism via the cytochrome P450 system.
    BMC Medical Genetics 07/2014; 15(1):76. DOI:10.1186/1471-2350-15-76 · 2.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Maraviroc is an anti-HIV drug that acts by blocking viral entry into target cells. Using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) several monooxygenated, dioxygenated and glucuronidated metabolites of maraviroc were identified both in vitro and in vivo. Characterization of the enzymes involved in the production of these metabolites determined that cytochrome P450 3A5 (CYP3A5) was the principal enzyme responsible for the formation of an abundant metabolite of maraviroc that resulted from oxygenation of the dichlorocyclohexane ring. For the formation of this metabolite the V(max) values for CYP3A4 and CYP3A5 were 0.04 and 0.93 pmole/min/pmole P450, and the K(m) values were 11.1 μM and 48.9 μM, respectively. Further, human liver microsomes isolated from donors homozygous for the loss-of-function CYP3A5*3 allele exhibited a 79% decrease in formation of this metabolite as compared to those homozygous for the wild-type CYP3A5*1 allele. In order to probe which divergent residues between CYP3A4 and CYP3A5 might play a role in the differential activities of these enzymes towards maraviroc mutations were introduced into both enzymes and metabolism of maraviroc was measured. A CYP3A5 L57F mutant exhibited a 61% decrease in the formation of this metabolite whereas formation by a CYP3A4 F57L mutant was increased by 337% as compared to wild-type. Taken together, these data provide novel insight into the biotransformation of maraviroc as well as the potential role of CYP3A4 and CYP3A5 divergent residues in the enzymatic activities of these two highly homologous enzymes.
    Drug metabolism and disposition: the biological fate of chemicals 08/2012; 40(12). DOI:10.1124/dmd.112.048298 · 3.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to evaluate the effect of the CYP3A5*3 allele on the pharmacokinetics of tacrolimus and amlodipine, and drug-drug interactions between them in healthy subjects. Pharmacokinetic drug interactions between tacrolimus and amlodipine were evaluated in a randomized, 3-period, 6-sequence crossover study in healthy Chinese volunteers according to CYP3A5 genotype. The single-dose and multiple-dose study were designed. A 96-hour pharmacokinetic study followed either tacrolimus or amlodipine dose, and the washout period between the study phases were 14 days. In the single-dose study, apparent oral clearance (CL/F) of tacrolimus (5mg) in CYP3A5 expressers was 3.8-fold (p=0.008) higher than that in CYP3A5 non-expressers. Amlodipine decreased mean tacrolimus CL/F in CYP3A5 expressers by 2.2-fold (p=0.005), while it had no effect on that in CYP3A5 non-expressers. The CL/F of amlodipine in CYP3A5 non-expressers was 2.0-fold (p=0.001) higher than that in CYP3A5 expressers. Tacrolimus increased mean amlodipine CL/F in CYP3A5 expressers by 1.4-fold (p=0.016) while it had no effect on that in CYP3A5 non-expressers. Tacrolimus slightly reduced the AUC(0-∞) of amlodipine in both CYP3A5 expressers and non-expressers. Dose adjustment of tacrolimus should be considered according to CYP3A5*3 genetic polymorphism when tacrolimus is coadministered with amlodipine.
    Drug Metabolism and Pharmacokinetics 02/2013; 28(5). DOI:10.2133/dmpk.DMPK-12-RG-148 · 2.57 Impact Factor
Show more