warfarin and abacavir

Several proofs of principle have established that pharmacogenetic testing for mutations altering expression and functions of genes associated with drug disposition and response can decrease the "trial-and-error" dosing and reduce the risk of adverse drug reactions. These proofs of principle include thiopurine methyltransferase and thiopurine therapy, dihydropyrimidine dehydrogenase/thymidylate synthase and 5-fluorouracil therapy, folate enzyme MTHFR and methotrexate therapy, UGT1A1 and irinotecan therapy and CYP450 2C9 and S-warfarin therapy. These evidences advocate for the prospective identification of mutations associated with drug response, serious adverse reactions and treatment failure. More recent evidence with the HLA basis of hypersensitivity to the retroviral agent abacavir demonstrates the potential of pharmacogenetic testing and its pharmacoeconomic implications. With the convergence of rising drug costs and evidence supporting the clinical benefits of pharmacogenetic testing, it will be important to demonstrate the improved net health outcomes attributed to the additional costs for this testing.

Topics: Antineoplastic Agents; Cytochrome P-450 Enzyme System; Dideoxynucleosides; Histocompatibility Testing; Humans; Mutation; Neoplasms; Pharmacogenetics; Warfarin

Topics: Antidepressive Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; Mercaptopurine; Pharmacogenetics; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Primaquine; Purine-Pyrimidine Metabolism, Inborn Errors; Succinylcholine; Warfarin

Human serum albumin (HSA) participates to heme scavenging, in turn HSA-heme binds gaseous diatomic ligands at the heme-Fe-atom. Here, the effect of abacavir and warfarin on denitrosylation kinetics of HSA-heme-Fe(II)-NO (i.e., k(off)) is reported. In the absence of drugs, the value of k(off) is (1.3+/-0.2) x 10(-4)s(-1). Abacavir and warfarin facilitate NO dissociation from HSA-heme-Fe(II)-NO, the k(off) value increases to (8.6+/-0.9) x 10(-4)s(-1). From the dependence of k(off) on the drug concentration, values of the dissociation equilibrium constant for the abacavir and warfarin binding to HSA-heme-Fe(II)-NO (i.e., K=(1.2+/-0.2) x 10(-3)M and (6.2+/-0.7) x 10(-5)M, respectively) were determined. The increase of k(off) values reflects the stabilization of the basic form of HSA-heme-Fe by ligands (e.g., abacavir and warfarin) that bind to Sudlow's site I. This event parallels the stabilization of the six-coordinate derivative of the HSA-heme-Fe(II)-NO atom. Present data highlight the allosteric modulation of HSA-heme-Fe(II) reactivity by heterotropic effectors.

Topics: Anticoagulants; Dideoxynucleosides; Humans; Iron; Kinetics; Nitric Oxide; Serum Albumin; Warfarin