title: Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels.
abstract: Individuals with lower inosine triphosphatase (ITPA) enzyme activity have a reduced likelihood of experiencing hemolytic anemia during hepatitis C virus (HCV) treatment containing ribavirin (RBV). Because ITPA degrades purines and RBV is a purine analogue, it is conceivable that ITPA activity may affect intracellular RBV concentrations. Here we assessed the association between ITPA activity phenotype and concentrations of RBV triphosphate (RBV-TP) in red blood cells (RBCs) during HCV treatment. RBV-TP was quantified in the RBCs of 177 HCV-infected individuals at a median (range) of 84 (19 to 336) days into HCV treatment that included RBV. Mean (SD) RBV-TP concentrations were 92.8 (51.6), 101.3 (53.5), 184.8 (84.5), and 197.7 (64.6) pmol/106cells for 100%, 60%, 30%, and ≤10% ITPA activity groups, respectively. Overall, RBV-TP was approximately 2-fold higher in patients with ≤30% ITPA activity compared to 100% activity (P < .0001). Despite higher RBV-TP levels, individuals with variant ITPA phenotypes had less anemia. The 100% activity group had, on average, a -2.20 g/dL drop in hemoglobin vs -1.43 g/dL (P = .04) for 60% activity, -1.14 g/dL (P = .008) for 30% activity, and -0.70 g/dL (P = .06) for ≤10% activity. This finding of higher RBV-TP concentrations in RBCs in ITPA variants was unexpected given that ITPA activity-deficient individuals have a reduced likelihood of RBV-induced anemia. It also refutes the hypothesis that the mechanism by which ITPA variants are protected against anemia is due to lower RBV-TP levels in RBCs.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Jimmerson
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.affiliation: Denver Health Medical Center, Denver, Colorado.
authors.forename: Aimee
authors.initials: A
authors.lastname: Truesdale
authors.affiliation: Denver Health Medical Center, Denver, Colorado.
authors.forename: Fafa
authors.initials: F
authors.lastname: Baouchi-Mokrane
authors.affiliation: Division of Clinical Care and Research, Institute of Human Virology, University of Maryland, Baltimore, Maryland.|Critical Care Medicine Department, Clinical Center, National Institute of Health, Bethesda, Maryland.
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
authors.affiliation: Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.|Critical Care Medicine Department, Clinical Center, National Institute of Health, Bethesda, Maryland.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Meissner
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institute of Health, Bethesda, Maryland.
authors.forename: Zayani
authors.initials: Z
authors.lastname: Sims
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.|Department of Pharmacy, University of Colorado Hospital, Aurora, Colorado.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Langness
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.
authors.forename: Ariel
authors.initials: A
authors.lastname: Hodara
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Aquilante
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Kiser
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071184:Pharmacogenomic Variants / Q000502:physiology*; D010641:Phenotype; D011755:Pyrophosphatases / Q000097:blood* / Q000235:genetics*; D012254:Ribavirin / Q000097:blood* / Q000627:therapeutic use; D000097630:Inosine Triphosphatase
chemical_list: D011755:Pyrophosphatases; D012254:Ribavirin; D000097630:Inosine Triphosphatase
keywords: ITPA activity; Intracellular pharmacology; Pharmacogenetics/Pharmacogenomics; Ribavirin triphosphate; SNPs; hemoglobin decline