title: Pharmacokinetics, dose-range, and mutagenicity studies of methylphenidate hydrochloride in B6C3F1 mice.
abstract: Methylphenidate hydrochloride (MPH) is one of the most frequently prescribed pediatric drugs for the treatment of attention deficit hyperactivity disorder. In a recent study, increased hepatic adenomas were observed in B6C3F1 mice treated with MPH in their diet. To evaluate the reactive metabolite, ritalinic acid (RA) of MPH and its mode of action in mice, we conducted extensive investigations on the pharmacokinetics (PK) and genotoxicity of the drug in B6C3F1 mice. For the PK study, male B6C3F1 mice were gavaged once with 3 mg/kg body weight (BW) of MPH and groups of mice were sacrificed at various time points (0.25-24 hr) for serum analysis of MPH and RA concentrations. Groups of male B6C3F1 mice were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm of MPH for 28 days to determine the appropriate doses for 24-week transgenic mutation studies. Also, the micronucleus frequencies (MN-RETs and MN-NCEs), and the lymphocyte Hprt mutants were determined in peripheral blood and splenic lymphocytes, respectively. Mice fed 4,000 ppm of MPH lost significant BW compared to control mice (P < 0.01). There was a significant increase in the average liver weights whereas kidneys, seminal vesicle, testes, thymus, and urinary bladder weights of mice fed higher doses of MPH were significantly lower than the control group (P < or = 0.05). There was no significant increase in either the Hprt mutant frequency or the micronucleus frequency in the treated animals. These results indicated that although MPH induced liver hypertrophy in mice, no genotoxicity was observed.
authors.affiliation: Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA. mugimane.manjanatha@fda.hhs.gov
authors.forename: Mugimane G
authors.initials: MG
authors.lastname: Manjanatha
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Shelton
authors.forename: Vasily N
authors.initials: VN
authors.lastname: Dobrovolsky
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Shaddock
authors.forename: Lynda G
authors.initials: LG
authors.lastname: McGarrity
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Twaddle
authors.forename: Chien-Ju
authors.initials: CJ
authors.lastname: Lin
authors.forename: James J
authors.initials: JJ
authors.lastname: Chen
authors.forename: Donald R
authors.initials: DR
authors.lastname: Mattison
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Morris
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000633:toxicity*; D051379:Mice; D009152:Mutagenicity Tests; D009929:Organ Size / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D008774:Methylphenidate; D007041:Hypoxanthine Phosphoribosyltransferase; C009189:ritalinic acid