Pharmacogenetics-Oriented Therapeutic Drug Monitoring of Digoxin in Critically ILL Patients

THis study was performed to outline the different MDR-1 (Multi-Urug Resistance-1) genotypes in a sample of 37 Egyptian patients, suffering from atrial fibrillation (AF) and/or congestive heart failure (CHF) and are using digoxin, to assess the role of MDR-1 genotypes polymorphism in affecting steady state serum digoxin therapeutic levels, and studying the consequences on patients clinical outcome. Two venous blood samples were drawn from each patient; the 1st sample was taken, on admission, for DNA extraction and genotyping and the 2 nd was taken, 6 hours post dose after reaching steady state concentration, for serum digoxin assay. Serum digoxin levels were assayed using EMIT 2000 analyzer, and MDR-1 genotyping was done using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Twenty patients (54.1%) showed serum digoxin levels within the therapeutic range, 12 patients (32.4%) showed serum digoxin levels under the minimum effective concentration ( 0.9 ng/ml), while 5 patients (13.5%) showed serum digoxin levels over maximum safety concentration ( 2 ng/ml), with P value of 0.0001 among the three groups. MDR-1 genotyping revealed ten patients (27%) carrying the homozygous mutant TT genotype, 27 patients (73%) carrying the heterozygous mutant CT genotype, with no patient showing the wild CC genotype. Allelic distribution showed 42% for the wild type C allele while 58% for the homozygous mutant T allele. Patients carrying the homozygous mutant TT genotype showed significantly lower serum digoxin levels compared with those carrying the heterozygous mutant CT genotype (P value: 0.009). Patients with significant improvement carried the CT genotype and had serum digoxin levels within the therapeutic range. In conclusion, patients with different MDR-1 genotypes had variations in their serum digoxin levels and identification of MDR-1 variations was found useful in predicting therapy outcome. We recommend further extensive work on large samples to study the important role of MDR-1 gene in affecting the disposition of different substrates, to be able for individualizing them according to the patients genetic profile in order to improve drug therapy and reduce inter-patient variability.