Vol. 30, Issue 12, 1470-1477, December 2002

Comparative Pharmacokinetic and Disposition Studies of [1-¹⁴C]1-Eicosanylcyclohexane, a Surrogate Mineral Hydrocarbon, in Female Fischer-344 and Sprague-Dawley Rats

Jason S. Halladay, Carl R. Mackerer, Lorraine E. Twerdok, and I. Glenn Sipes

Department of Pharmacology, University of Arizona, Tucson, Arizona (J.S.H., I.G.S.); and American Petroleum Institute White Oils and Waxes Research Group, Washington, DC (C.R.M., L.E.T.)

White oils or waxes [mineral hydrocarbons (MHCs)] with substantial levels of saturated hydrocarbons in the range of C18 to C32 have produced hepatic microgranulomas and lymph node microgranulomas (also referred to as histiocytosis) after repeated administration to female Fischer-344 (F-344) rats. Female Sprague-Dawley (S-D) rats are less sensitive to these MHC-induced hepatic and lymph node effects. Studies reported herein characterized the pharmacokinetics and disposition of a representative C-26 MHC, [1-¹⁴C]1-eicosanylcyclohexane ([¹⁴C]EICO), in these two rat strains. Female F-344 and S-D rats were administered by oral gavage either a high (1.80 g/kg) or a low (0.18 g/kg) dose of MHC in olive oil (1:4, v/v) containing [¹⁴C]EICO as a tracer. Blood, urine, feces, liver, and mesenteric lymph nodes (MLNs) were analyzed for [¹⁴C]EICO and ¹⁴C-metabolites. After the high dose, F-344 rats had a higher blood C_max of [¹⁴C]EICO, a longer time to C_max, and a greater area under the systemic blood concentration-time curve from zero to time infinity compared with S-D rats. After the low dose, F-344 rats displayed a unique triphasic blood concentration-time profile, meaning two distinct C_max values were observed. Fecal excretion was the major route of [¹⁴C]EICO elimination for both rat strains (70-92% of the dose). S-D rats eliminated the majority of [¹⁴C]EICO metabolites recovered in the urine by 16 h (8-17% of the dose), whereas F-344 rats did not excrete the same amount until 72 to 96 h. Beyond 24 h, a greater level of [¹⁴C]EICO was recovered in livers of F-344 rats; at 96 h, 3 and 0.1% of the dose was retained in livers of F-344 and S-D rats, respectively. The major urinary metabolites of EICO in both rat strains were identified as 12-cyclohexyldodecanoic acid and 10-cyclohexyldecanoic acid. Based on the pharmacokinetic parameters and disposition profiles, the data indicate inherent strain differences in the total systemic exposure, rate of metabolism, and hepatic and lymph node retention of [¹⁴C]EICO, which may be associated with the different strain sensitivities to the formation of liver granulomas and MLN histiocytosis.