title: Clinical pharmacology of tenofovir clearance: a pharmacokinetic/pharmacogenetic study on plasma and urines.
abstract: The HIV virus and hepatitis B virus nucleotide reverse transcriptase inhibitor tenofovir has been associated with proximal tubular toxicity; the latter was found to be predicted by plasma concentrations and with single-nucleotide polymorphisms in transporters-encoding genes. A cross-sectional analysis in adult HIV-positive patients with estimated creatinine clearance >60 ml min-1was performed. Twelve-hour plasma and urinary tenofovir concentrations and single-nucleotide polymorphisms in several transporter-encoding genes were analysed. In 289 patients 12-h tenofovir plasma, urinary and urinary to plasma ratios were 69 ng ml-1(interquartile range 51.5-95), 24.3 mg ml-1(14.3-37.7) and 384 (209-560). At multivariate analysis estimated creatinine clearance, protease inhibitors co-administration and SLC28A2 CT/TT genotypes were independently associated with plasma tenofovir exposure; ABCC10 GA/AA genotypes and protease inhibitor co-administration were independently associated with the urinary to plasma tenofovir ratio. Tenofovir clearance was associated with genetic polymorphisms in host genes and with co-administered drugs: if confirmed by ongoing studies these data may inform treatment tailoring and/or dose reductions.
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Calcagno
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Cusato
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Marinaro
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Trentini
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Alcantarini
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mussa
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Simiele
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: D'Avolio
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Di Perri
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bonora
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D003404:Creatinine / Q000097:blood / Q000652:urine; D003430:Cross-Sectional Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016014:Linear Models; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D015999:Multivariate Analysis; D010597:Pharmacogenetics / Q000379:methods*; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011480:Protease Inhibitors / Q000493:pharmacokinetics; D065667:Renal Elimination; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D018570:Risk Assessment; D012307:Risk Factors; D000068698:Tenofovir / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D019380:Anti-HIV Agents; D003404:Creatinine; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011480:Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; C421142:ABCC10 protein, human; C065171:cif nucleoside transporter