Development of a Physiologically Based Pharmacokinetic Model for Ethylene Glycol and Its Metabolite, Glycolic Acid, in Rats and Humans

Abstract

An extensive database on the toxicity and modes of action of ethylene glycol (EG) has been developed over the past several decades. Although renal toxicity has long been recognized as a potential outcome, in recent years developmental toxicity, an effect observed only in rats and mice, has become the subject of extensive research and regulatory reviews to establish guidelines for human exposures. The developmental toxicity of EG has been attributed to the intermediate metabolite, glycolic acid (GA), which can become a major metabolite when EG is administered to rats and mice at high doses and dose rates. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to integrate the extensive mode of action and pharmacokinetic data on EG and GA for use in developmental risk assessments. The resulting PBPK model includes inhalation, oral, dermal, intravenous, and subcutaneous routes of administration. Metabolism of EG and GA were described in the liver with elimination via the kidneys. Metabolic rate constants and partition coefficients for EG and GA were estimated from in vitro studies. Other biochemical constants were optimized from appropriate in vivo pharmacokinetic studies. Several controlled rat and human metabolism studies were used to validate the resulting PBPK model. When internal dose surrogates were compared in rats and humans over a broad range of exposures, it was concluded that humans are unlikely to achieve blood levels of GA that have been associated with developmental toxicity in rats following occupational or environmental exposures.

The Effects of Dose and Route on the Toxicokinetics and Disposition of 1-Butyl-3-methylimidazolium Chloride in Male F-344 Rats and Female B6C3F1 Mice

“…The estimated systemic clearance rate of Bmim-Cl determined in the studies reported here suggests that Bmim-Cl may also be secreted from the nephron by OCTs. The estimated clearance rates of Bmim-Cl (CL b ϭ 7.4 -11.9 ml/min) approached reported values for renal blood flow (12 ml/min) (Corley et al, 2005). Because glomerular filtration is approximately equivalent to 12% of renal blood flow (Shargel and Yu, 1992;Caron and Kramp, 1999), glomerular filtration of Bmim-Cl cannot explain the efficient systemic clearance and rapid urinary elimination of Bmim-Cl.…”

Effects of Dose and Route on the Disposition and Kinetics of 1-Butyl-1-methylpyrrolidinium Chloride in Male F-344 Rats

“…The blood clearance for Bmim-Cl, NBuPy-Cl, and BmPy-Cl exceeds published values for the glomerular filtration rate (0.5-1.2 ml/min/100-g rat) (Corley et al, 2005), suggesting a secretory mechanism for these ILs. Secretion is mediated by a variety of transporters, many of which are known to be critical in the elimination of a variety of clinically used drugs (Jonker and Schinkel, 2004) as well as occupationally and environmentally relevant compounds (Prasad et al, 2007).…”

In Vitro Glucuronidation of 2,2-Bis(bromomethyl)-1,3-propanediol by Microsomes and Hepatocytes from Rats and Humans

“…The mean value for the overall CL H of BMP by hepatic microsomes from male and female F-344 rats was estimated to be 23.5 and 18.5 ml/min/kg. This value indicates a clearance of BMP in rats that corresponds to approximately 50% of the rat liver blood flow that was reported to be 45 ml/min/kg (Corley et al, 2005). These estimated hepatic CL H values suggest a liver extraction ratio of 0.4 to 0.5 for rats.…”

“…The calculated CL was scaled up to total liver microsomal protein per kilogram (CL int ) by assuming a rat liver weight of 30 g/kg b.wt. and a conversion factor of 45 mg of microsomal protein per 1 g of liver (Corley et al, 2005). The total hepatic clearance (CL H ) was calculated using the following formula from the well stirred model:…”

“…The rat hepatic blood flow (Q) was assumed to be 45 ml/min/kg (Corley et al, 2005), and f u was determined to be 0.6 by a method described previously by Cheng et al (2009). fu inc was estimated to be 0.94 (Hallifax and Houston, 2006).…”