title: The genetic toxicology of methylphenidate hydrochloride in non-human primates.
abstract: The studies presented in this work were designed to evaluate the genetic toxicity of methylphenidate hydrochloride (MPH) in non-human primates (NHP) using a long-term, chronic dosing regimen. Thus, approximately two-year old, male rhesus monkeys of Indian origin were orally exposed to MPH diluted in the electrolyte replenisher, Prang, five days per week over a 20-month period. There were 10 animals per dose group and the doses were (1) control, Prang only, (2) low, 0.15 mg/kg of MPH twice per day increased to 2.5mg/kg twice per day and (3) high, 1.5 mg/kg of MPH twice per day increased to 12.5 mg/kg twice per day. Blood samples were obtained from each animal to determine the base-line serum levels of MPH and the major metabolite of MPH in NHP, ritalinic acid (RA). In addition, the base-line frequency of micronucleated erythrocytes (MN-RETs) by flow cytometry, HPRT mutants by a lymphocyte cloning assay, and chromosome aberrations by FISH painting were determined from peripheral blood samples. Once dosing began, the serum levels of MPH and its major metabolite, RA, were determined monthly. The MN-RET frequency and health parameters (CBC, serum chemistries) were also determined monthly. HPRT mutant and chromosome aberration frequencies were measured every three months. CBC values and serum chemistries, with the exception of alanine amino transferase, were within normal limits over the course of drug exposure. The final plasma levels of MPH were similar to those produced by the pediatric dose of 0.3 microg/ml. No significant increases in the frequencies of MN-RETs, HPRT mutants, or chromosome aberrations were detected in the treated animals compared to the control animals over the 20-month exposure period.
authors.affiliation: Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, United States. suzanne.morris@fda.hhs.gov
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Morris
authors.forename: Vasily N
authors.initials: VN
authors.lastname: Dobrovolsky
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Shaddock
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Mittelstaedt
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Bishop
authors.forename: Mugimane G
authors.initials: MG
authors.lastname: Manjanatha
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Shelton
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Twaddle
authors.forename: James J
authors.initials: JJ
authors.lastname: Chen
authors.forename: Chien-Ju
authors.initials: CJ
authors.lastname: Lin
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.forename: William
authors.initials: W
authors.lastname: Slikker
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Hotchkiss
authors.forename: Dayton
authors.initials: D
authors.lastname: Petibone
authors.forename: James D
authors.initials: JD
authors.lastname: Tucker
authors.forename: Donald R
authors.initials: DR
authors.lastname: Mattison
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D002869:Chromosome Aberrations / Q000139:chemically induced*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D008774:Methylphenidate / Q000494:pharmacology*; D015162:Micronucleus Tests; D009154:Mutation / Q000235:genetics; D011323:Primates; D053719:Tandem Mass Spectrometry
chemical_list: D008774:Methylphenidate; D007041:Hypoxanthine Phosphoribosyltransferase