title: Ethambutol plasma and intracellular pharmacokinetics: A pharmacogenetic study.
abstract: We evaluated ethambutol plasma and intracellular pharmacokinetic according to single nucleotide polymorphisms in ABCB1, OATP1B1, PXR, VDR, CYP24A1 and CYP27B1 genes. Mycobacterium tubercolosis infected patients were enrolled. Standard weight-adjusted antitubercular treatment was administered intravenously for 2 weeks and then orally. Allelic discrimination was performed by real-time PCR. Ethambutol plasma and intracellular concentrations were measured by UPLC-MS/MS methods. Twenty-four patients were included. Considering weeks 2 and 4, median plasma Ctrough were 73 ng/mL and 247 ng/mL, intracellular Ctrough were 16,863 ng/mL and 13,535 ng/mL, plasma Cmax were 5627 ng/mL and 2229 ng/mL, intracellular Cmax were 133,830 ng/mL and 78,544 ng/mL. At week 2, ABCB1 3435 CT/TT (p=0.023) and CYP24A1 8620 AG/GG (p=0.030) genotypes for plasma Ctrough, BsmI AA (p=0.036) for intracellular Ctrough and BsmI AA (p<0.001) and ApaI AA (p=0.048) for intracellular Cmax, remained in linear regression analysis as predictive factors. Concerning week 4 only ABCB1 3435 CT/TT (p=0.035) and Cdx2 AG/GG (p=0.004) genotypes for plasma Ctrough and BsmI AA (p=0.028) for plasma Cmax were retained in final regression model. We reveal, for the first time, the possible role of single nucleotide polymorphisms on ethambutol plasma and intracellular concentrations; this may further the potential use of pharmacogenetic for tailoring antitubercular treatment.
authors.affiliation: Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Fatiguso
authors.affiliation: Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy. Electronic address: sarah.allegra@gmail.com.
authors.forename: Sarah
authors.initials: S
authors.lastname: Allegra
authors.affiliation: Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.affiliation: Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Baietto
authors.affiliation: Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Motta
authors.affiliation: Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Favata
authors.affiliation: Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cusato
authors.affiliation: Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.affiliation: Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Giovanni Di
authors.initials: GD
authors.lastname: Perri
authors.affiliation: Department of Medical Sciences, Unit of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D004977:Ethambutol / Q000097:blood* / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D013997:Time Factors; D014376:Tuberculosis / Q000097:blood* / Q000235:genetics*; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D000074435:Peroxisome-Targeting Signal 1 Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; C503999:SLCO1B1 protein, human; C579457:VDR protein, human; D004977:Ethambutol; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
keywords: ABCB1; BsmI; CYP24A1; Cdx2; Ethambutol; FokI