Dataset Information

Warfarin-amiodarone drug-drug interactions: determination of [I](u)/K(I,u) for amiodarone and its plasma metabolites.

ABSTRACT: A retrospective clinical evaluation in a cohort of 73 patients receiving stable anticoagulation therapy showed that the addition/elimination of amiodarone resulted in a 6-65% change in warfarin dose requirement. To evaluate the roles of amiodarone and its circulating metabolites in this highly variable inhibitory drug interaction, a liquid chromatography-electrospray ionization-tandem mass spectrometry assay was developed for the quantitation of low concentrations of these compounds in human plasma, using newly synthesized deuterated analogs as internal standards. Inhibition constant (K(I)) values were determined for the inhibition of (S)-warfarin 7-hydroxylation in human liver microsomes by the parent drug and its metabolites, and the unbound drug fractions (f(u)) were measured in order to calculate the ratio of unbound plasma concentration to the microsomal K(I) for the unbound drug ([I](u)/K(I,u)). From these ratios, we predict that a minor metabolite of amiodarone, namely, N,N-didesethylamiodarone (DDEA), is a major contributor to the interaction between warfarin and amiodarone.

SUBMITTER: McDonald MG

PROVIDER: S-EPMC3900249 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Warfarin-amiodarone drug-drug interactions: determination of [I](u)/K(I,u) for amiodarone and its plasma metabolites.

McDonald M G MG Au N T NT Wittkowsky A K AK Rettie A E AE

Clinical pharmacology and therapeutics 20120307 4

A retrospective clinical evaluation in a cohort of 73 patients receiving stable anticoagulation therapy showed that the addition/elimination of amiodarone resulted in a 6-65% change in warfarin dose requirement. To evaluate the roles of amiodarone and its circulating metabolites in this highly variable inhibitory drug interaction, a liquid chromatography-electrospray ionization-tandem mass spectrometry assay was developed for the quantitation of low concentrations of these compounds in human pla ...[more]

PMID: 22398967

Similar Datasets

Project description:Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained. CYP2C9*8, CYP2C9*9, CYP2C9*11, and the CYP2C cluster SNP rs12777823 passed the Bonferroni-adjusted replication significance threshold (p < 3.21E-04) for warfarin/metabolite ratios. In an exploratory GWAS analysis, 373 unique SNPs in 13 genes, including CYP2C9*8, passed the Bonferroni-adjusted genome-wide significance threshold (p < 3.846E-9), with 325 (87%, all located on chromosome 10) SNPs being associated with the S-warfarin/R-warfarin outcome (top SNP rs11188082, CYP2C19 intron variant, p = 1.55E-17). Approximately 69% of these SNPs were in linkage disequilibrium (r 2 > 0.8) with CYP2C9*8 (n = 216) and rs12777823 (n = 8). Using a pharmacokinetic approach, we have shown that variants other than CYP2C9*2 and CYP2C9*3 are more important in sub-Saharan black-Africans, mainly due to the allele frequencies. In exploratory work, we conducted the first warfarin pharmacokinetics-related GWAS in sub-Saharan Africans and identified novel SNPs that will require external replication and functional characterization before they can be considered for inclusion in warfarin dosing algorithms.

Project description:BackgroundAlectinib, crizotinib, and ceritinib, are anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) that exhibit high protein binding, and their metabolism is associated with the cytochrome P450 (CYP) isoenzymes 2C9 or 3A4. The plasma protein binding rate of warfarin, which is used to prevent and treat venous thromboembolism, is also high. Warfarin is a racemate of S-warfarin and R-warfarin, which are metabolized by CYP2C9 and CYP3A4, respectively. Reports on the drug interactions between each of the above-mentioned ALK-TKIs and warfarin with concurrent use of bucolome are currently lacking.Case presentationWe report a case of a patient receiving warfarin and bucolome, whose international normalized ratio (INR) increased after sequential treatment with alectinib, crizotinib, and ceritinib. The patient was a 61-year-old man with a history of aortic valve regurgitation, who was receiving warfarin treatment following aortic valve replacement. Bucolome, which can enhance the effect of warfarin, was also used simultaneously. The patient was diagnosed with primary lung adenocarcinoma, and ALK rearrangement was detected during second-line chemotherapy. After progression of the disease with chemotherapy, sequential treatment with alectinib, crizotinib, and ceritinib was initiated. Pretreatment INR values were in the therapeutic range (target INR of 2-3) but increased to supratherapeutic levels each time after initiation of alectinib, crizotinib, or ceritinib treatment. Adjustment of warfarin dose or discontinuation of bucolome were necessary to maintain the therapeutic INR range. There were no serious bleeding events or substantial changes in dietary intake. Displacement of plasma protein binding or competitive inhibition of metabolism by alectinib, crizotinib, and ceritinib could increase the plasma concentration of the unbound form of warfarin, resulting in high INR values. In addition, alectinib, crizotinib, and ceritinib might cause displacement of bucolome from plasma proteins, followed by displacement of warfarin or inhibition of warfarin metabolism caused by the unbound form of bucolome.ConclusionsClose monitoring of INR and adjustment of warfarin dosage are needed during treatment with alectinib, crizotinib, or ceritinib in patients who receive warfarin with concurrent use of bucolome.

Dataset Information

Warfarin-amiodarone drug-drug interactions: determination of [I](u)/K(I,u) for amiodarone and its plasma metabolites.

Publications

Warfarin-amiodarone drug-drug interactions: determination of [I](u)/K(I,u) for amiodarone and its plasma metabolites.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets