title: Effects of SLC22A1 Polymorphisms on Metformin-Induced Reductions in Adiposity and Metformin Pharmacokinetics in Obese Children With Insulin Resistance.
abstract: Steady-state population pharmacokinetics of a noncommercial immediate-release metformin (hydrochloride) drug product were characterized in 28 severely obese children with insulin resistance. The concentration-time profiles with double peaks were well described by a 1-compartment model with 2 absorption sites. Mean population apparent clearance (CL/F) was 68.1 L/h, and mean apparent volume of distribution (V/F) was 28.8 L. Body weight was a covariate of CL/F and V/F. Estimated glomerular filtration rate was a significant covariate of CL/F (P < .001). SLC22A1 genotype did not significantly affect metformin pharmacokinetics. The response to 6 months of metformin treatment (HbA1c, homeostasis model assessment for insulin resistance, fasting insulin, and glucose changes) did not differ between SLC22A1 wild-type subjects and carriers of presumably low-activity SLC22A1 alleles. However, SLC22A1 variant carriers had smaller reductions in percentage of total trunk fat after metformin therapy, although the percentage reduction in trunk fat was small. The median % change in trunk fat was -2.20% (-9.00% to 0.900%) and -1.20% (-2.40% to 7.30%) for the SLC22A1 wild-type subjects and variant carriers, respectively. Future study is needed to evaluate the effects of SLC22A1 polymorphisms on metformin-mediated weight reduction in obese children.
authors.affiliation: Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Wai Johnn
authors.initials: WJ
authors.lastname: Sam
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.|Institute of Pharmacognosy, University of Szeged, Szeged, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Roza
authors.affiliation: Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, MD, USA.|Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Yuen Yi
authors.initials: YY
authors.lastname: Hon
authors.affiliation: Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Raul M
authors.initials: RM
authors.lastname: Alfaro
authors.affiliation: Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, MD, USA.|Office of the Clinical Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Karim A
authors.initials: KA
authors.lastname: Calis
authors.affiliation: Nuclear Medicine Division, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Reynolds
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Yanovski
mesh_terms: D050154:Adiposity / Q000187:drug effects* / Q000235:genetics*; D001835:Body Weight; D002648:Child; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics*; D050811:Octamer Transcription Factor-1 / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics; D015431:Weight Loss / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D008687:Metformin
keywords: metformin; obesity; pediatric; pharmacogenomics; pharmacokinetics; weight loss