title: Impact on L-carnitine Homeostasis of Short-term Treatment with the Pivalate Prodrug Tenofovir Dipivoxil.
abstract: Pivalate-generating prodrugs have been suggested to cause clinically significant hypocarnitinaemia. Tenofovir dipivoxil, a novel ester prodrug of tenofovir, can be used for treatment for hepatitis B and HIV infection and it was necessary to evaluate the effect of its treatment on carnitine homeostasis. We sought to investigate the effect of Class 1 drug tenofovir dipivoxil on endogenous L-carnitine level during a 72-hr test in healthy Chinese volunteers and to establish a suitable dose of L-carnitine nutritional supplement for patients who were administered short-term tenofovir dipivoxil tablets for treatment for hepatitis B and herpes simplex virus infection. Tenofovir dipivoxil was administered in one of eight dosing regimens (single dose 150, 300 and 600 mg, multiple dose 300, 450, and 600 mg, multiple dose 450 (600) mg tenofovir dipivoxil and 0.5 g L-carnitine) to gender-balanced groups of 84 healthy Chinese volunteers. Plasma concentrations of L-carnitine were quantified before, during and after treatment. Plasma L-carnitine concentrations fell during tenofovir dipivoxil dosing. The nadir in L-carnitine concentration was dependent on the dose of tenofovir dipivoxil and it decreased from 6.1 ± 0.6 to 4.4 ± 0.8 μg/ml, 6.1 ± 1.8 to 3.3 ± 1.2 μg/ml, 6.2 ± 0.6 to 2.5 ± 0.5 μg/ml for single doses of 150, 300, 600 mg tenofovir dipivoxil tablets and from 6.0 ± 1.4 to 2.1 ± 1.5 μg/ml, 6.2 ± 0.4 to 0.9 ± 0.5 μg/ml for multiple doses of 450, 600 mg tenofovir dipivoxil tablets, respectively. Short-term administration of tenofovir dipivoxil results in hypocarnitinaemia and increased losses of carnitine in resulting of minor adverse events of decreased food appetite, nausea, abdominal distention and muscle weakness.
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Jia
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Cheng-Tao
authors.initials: CT
authors.lastname: Lu
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Zhao
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Ai-Dong
authors.initials: AD
authors.lastname: Wen
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhi-Fu
authors.initials: ZF
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
authors.forename: Tai-Jun
authors.initials: TJ
authors.lastname: Hang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002331:Carnitine / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006509:Hepatitis B / Q000188:drug therapy; D006561:Herpes Simplex / Q000188:drug therapy; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008297:Male; D063065:Organophosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000494:pharmacology*; D000068698:Tenofovir
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; D000068698:Tenofovir; D000225:Adenine; D002331:Carnitine