title: Human biofluid concentrations of mono(2-ethylhexyl)phthalate extrapolated from pharmacokinetics in chimeric mice with humanized liver administered with di(2-ethylhexyl)phthalate and physiologically based pharmacokinetic modeling.
abstract: Di(2-ethylhexyl)phthalate (DEHP) is a reproductive toxicant in male rodents. The aim of the current study was to extrapolate the pharmacokinetics and toxicokinetics of mono(2-ethylhexyl)phthalate (MEHP, a primary metabolite of DEHP) in humans by using data from oral administration of DEHP to chimeric mice transplanted with human hepatocytes. MEHP and its glucuronide were detected in plasma from control mice and chimeric mice after single oral doses of 250mg DEHP/kg body weight. Biphasic plasma concentration-time curves of MEHP and its glucuronide were seen only in control mice. MEHP and its glucuronide were extensively excreted in urine within 24h in mice with humanized liver. In contrast, fecal excretion levels of MEHP glucuronide were high in control mice compared with those with humanized liver. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated urine MEHP concentrations in humans were consistent with reported concentrations. This research illustrates how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of pharmacokinetics or toxicokinetics of the primary or secondary metabolites of DEHP.
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors: Koichiro
authors: K
authors: Adachi
authors: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan.
authors: Hiroshi
authors: H
authors: Suemizu
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors: Norie
authors: N
authors: Murayama
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors: Makiko
authors: M
authors: Shimizu
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. Electronic address: hyamazak@ac.shoyaku.ac.jp.
authors: Hiroshi
authors: H
authors: Yamazaki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000652:urine; D005243:Feces / Q000737:chemistry; D006801:Humans; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation; D051379:Mice
chemical_list: D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate
keywords: Allometric scaling; PBPK modeling; Phthalate; Species difference; Urine