title: The pharmacokinetic profile of methylphenidate use in pregnancy: A study in mice.
abstract: The purpose of this study was to quantify the amounts of the d- and l-threo enantiomers of methylphenidate in maternal plasma, placenta, and maternal and fetal brain tissue following prenatal exposure and to establish a pharmacokinetic profile for MPH during pregnancy. Due to increasing rates of use of methylphenidate amongst females of childbearing age, it is important to understand the extent of exposure to the fetus. Briefly, pregnant mice were injected with 5 mg/kg methylphenidate at 18 days gestation, and tissue was collected 1, 5, 10, 30, 60, and 120 min following injection. Methylphenidate was extracted from tissue via solid phase extraction, and concentrations were determined using liquid chromatography-mass spectrometry (LC-MS). Because methylphenidate is administered as a racemic mixture of d- and l-threo enantiomers and the d-enantiomer is more pharmacologically active, the enantiomers were quantified separately. Interestingly, we found that methylphenidate does cross the placenta and enter the fetal brain. Although the highest concentrations were achieved in maternal brain, the concentrations of d- and l-methylphenidate in fetal brain were comparable to those of maternal plasma. Additionally, both d- and l-methylphenidate had longer half-lives in placenta than in maternal or fetal brain. Interestingly, there was a bimodal peak in maternal brain concentrations, at 5 min and again at 60 min, which was not observed in maternal plasma. Finally, the total exposure (as represented by area under the curve) was statistically significantly higher for the active d-enantiomer than the l-enantiomer in maternal brain tissue. In conclusion, methylphenidate crosses the placenta and reaches measurable concentrations in fetal brain. Although long-term behavioral and developmental studies are needed to determine specific outcomes of prenatal exposure, discussion with pregnant patients on the potential risks of methylphenidate exposure is warranted.
authors.affiliation: Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, Box 70594, East Tennessee State University, Johnson City, TN, United States.
authors.forename: Haley T
authors.initials: HT
authors.lastname: Peters
authors.affiliation: Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, Box 70594, East Tennessee State University, Johnson City, TN, United States.
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Strange
authors.affiliation: Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, Box 70594, East Tennessee State University, Johnson City, TN, United States.
authors.forename: Stacy D
authors.initials: SD
authors.lastname: Brown
authors.affiliation: Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, Box 70594, East Tennessee State University, Johnson City, TN, United States. Electronic address: pond@etsu.edu.
authors.forename: Brooks B
authors.initials: BB
authors.lastname: Pond
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000196:embryology; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics* / Q000633:toxicity; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008431:Maternal-Fetal Exchange / Q000187:drug effects* / Q000502:physiology; D008774:Methylphenidate / Q000493:pharmacokinetics* / Q000633:toxicity; D051379:Mice; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate
keywords: Chiral separation; High pressure liquid chromatography–tandem mass spectrometry; Methylphenidate; Pharmacokinetics; Prenatal