Inhalation pharmacokinetics based on gas uptake studies

Abstract

The pharmacokinetics of ethylene and 1,3-butadiene were studied in male Sprague-Dawley rats by use of a closed inhalation chamber system. Both compounds showed saturable metabolism when untreated rats were used. "Linear" pharmacokinetics applied at exposure concentrations below 800 ppm ethylene and below 1,000 ppm 1,3-butadiene. A constant elimination rate, indicative of metabolic saturation, occurred at concentrations higher than 1,000 ppm ethylene or 1,500 ppm 1,3-butadiene. Pretreatment with aroclor 1254 (polychlorinated biphenyls) increased Vmax for both compounds. For 1,3-butadiene, no saturation of metabolic capacity was observed with exposure concentrations up to 12,000 ppm when the rats were pretreated with aroclor 1254. A comparison with previous studies on ethane and n-pentane suggested that introduction of a double bond into a saturated aliphatic hydrocarbon increased the rate of metabolism under conditions in vivo.

A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites

“…The model simulations were in good agreement with clearance of various concentrations of BD or EB from closed chambers holding five or eight mice [26,37,34] and from chambers holding one or two rats [4,34] (data not shown).…”

Kinetics of Ethylene and Ethylene Oxide in Subcellular Fractions of Lungs and Livers of Male B6C3F1 Mice and Male Fischer 344 Rats and of Human Livers

“…If, however, one bears in mind the values of the suicide inactivation constant k 4 of the ET-metabolizing CYP2E1 (Table 2), one has to expect that the amount of hepatic CYP2E1, which is available for the ET oxidation, decreases in between 11 min (humans) and 18 min (mice) to about one third of the initial status at very high ET concentrations. In gas uptake studies with ET in rats (Bolt et al , 1984) or mice (Artati et al , 2009), this effect could not be recognized from the concentration-time courses of ET in the atmosphere because it occurs within the initial phase during which the gas enriches in the organism. Predicted K m concentrations in the atmosphere are 3.8- to 7.4-fold higher than actually determined in vivo .…”

“…c K m (ppm) was calculated by dividing the in Table 1 given K m (mmol/l suspension) by the in vivo obtained steady-state bioaccumulation factor K st , which gives the ratio of the average ET concentration in the body at low ET exposure concentrations to the ET exposure concentration in the atmosphere— K st = 0.55 (mouse, to be published), K st = 0.50 (rat, Bolt et al , 1984), and K st = 0.33 (human, Filser et al , 1992)—and by multiplication with 24,450 ml, the molar volume of an ideal gas at 25°C.…”

“…Brugnone et al (1985, 1986) reported EO concentrations in blood and ratios of alveolar to atmospheric EO concentrations in EO-exposed workers. Gas uptake experiments were also conducted to investigate in rats the kinetics of ET (Andersen et al , 1980; Bolt et al , 1984) and of EO (Filser and Bolt, 1984; Krishnan et al , 1992). EO was rapidly eliminated following first-order kinetics at EO concentrations of up to at least 100 ppm.…”

“…ET showed saturation kinetics that could be described according to Michaelis and Menten by V max and an apparent Michaelis constant ( K m ). The metabolic elimination of ET was quantitatively inhibited following pretreatment with sodium diethyldithiocarbamate; V max was doubled after pretreatment with a mixture of polychlorinated biphenyls (Bolt et al , 1984). These results hinted to a CYP-mediated metabolism of ET, later confirmed by Fennell et al (2004).…”