Pharmacokinetics of inhaled styrene in human volunteers

Ramsey, John C.; Young, John; Karbowski, R.J.; Chenoweth, Maynard B.; McCarty, Leslie P.; Braun, Werner

doi:10.1016/0041-008x(80)90381-6

Cited by 79 publications

(32 citation statements)

References 7 publications

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“…Both the rate of distribution and the rate of elimination decreased with increasing dose, while the apparent volume of distribution was unchanged (47). It has further been demonstrated that the clearance of styrene in the rat becomes saturated after exposure to between 200 and 600 ppm for 6 h and results in an abrupt change in its steadystate level in blood at higher doses (30). This phenomenon can mainly be ascribed to a limited metabolic capacity, especially of the cytochrome P-450 system, which appears to be saturable also in the mouse.…”

Section: (29)mentioning

confidence: 99%

Tissue distribution of styrene, styrene glycol and more polar styrene metabolites in the mouse.

Löf¹,

Gullstrand²,

Nordqvist³

1983

Scand J Work Environ Health

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LOF A, GULLSTRAND E, BYFALT NORDQVIST M. Tissue distribution of styrene, styrene glycol and more polar styrene metabolites in the mouse. Scand j work environ health 9 (1983) 419-430. A primary objective of the present investigation was to detennine the tissue distribution of styrene, styrene glycol, and more polar metabolites in mice at different times (0.5-5 h) after the intraperitoneal administration of styrene (3.3 mmoll kg). Another aim was to determine the dose dependence of the metabolite pattern of styrene in the different tissues. The dose range chosen was 1.1-4.9 mmol of styrenelkg administered intraperitoneally, and the time delay 2 h after dosing. The highest initial concentrations of unchanged styrene were found in adipose tissue, pancreas, liver, and brain. Styrene glycol reached its maximum concentration within 1 h in most tissues. The levels in the kidneys, lungs, pancreas, and liver far exceeded those in subcutaneous adipose tissue. Only in the liver and kidneys was a notable amount of styrene glycol conjugated. Polar metabolites occurred to a considerable extent in the liver, kidneys, lungs, and plasma. The concentration of unmetabolized styrene seemed to increase exponentially with the dose in subcutaneous adipose tissue, liver, kidneys, lungs, and brain. No tendency towards a decreased relative occurrence of styrene glycol was observed at higher doses. However, when the dose was increased, the more polar metabolites occurred at relatively lower levels in all tissues except brain.

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Section: (29)mentioning

confidence: 99%

Tissue distribution of styrene, styrene glycol and more polar styrene metabolites in the mouse.

Löf¹,

Gullstrand²,

Nordqvist³

1983

Scand J Work Environ Health

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show abstract

“…After absorption, styrene is metabolized within hours by the liver. The main urinary excretion products are mandelic acid and phenylglyoxylic acid, which have been used in monitoring workplace exposure (ATSDR, 2007;Brugnone et al, 1993;Ramsey et al, 1980). The U.S. EPA has established a drinking water and other environmental standards for styrene.…”

Section: General Informationmentioning

confidence: 99%

Estimating perchlorate exposure from food and tap water based on US biomonitoring and occurrence data

Huber

Blount

Mage

et al. 2010

J Expo Sci Environ Epidemiol

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“…Most importantly, CYP2E1 activates many xenobiotics to hepatotoxic or carcinogenic products (Lieber, 1997). Also, a wide variety of CYP2E1 substrates are known to exhibit saturation kinetics (Ramsey and Young, 1978;Kirschman et al, 1986;Kreiling et al, 1986;Lof and Johanson, 1993;Dekant et al, 1995;Whysner et al, 1996;Lee et al, 2000;Vittozzi et al, 2000;Rappaport et al, 2002).…”

mentioning

confidence: 99%

Saturation Toxicokinetics of Thioacetamide: Role in Initiation of Liver Injury

Chilakapati

Shankar²,

Korrapati³

et al. 2005

Drug Metabolism and Disposition

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ABSTRACT:Thioacetamide (TA), a potent centrilobular hepatotoxicant, undergoes a two-step bioactivation mediated by microsomal CYP2E1 to TA sulfoxide (TASO), and further to TA-S,S-dioxide (TASO 2 ), a reactive metabolite that initiates cellular necrosis. Our earlier studies showed that bioactivation-mediated liver injury of TA is not doseproportional. The objective of this study was to examine whether increasing doses of TA lead to enzyme saturation, thereby resulting in lack of dose-response for injury: bioactivation of TA 3 TASO 3 TASO 2 may follow zero-order kinetics. A 12-fold dose range of TA (50, 300, and 600 mg/kg i.p.) was injected into male SpragueDawley rats. TA and TASO were quantified in plasma, liver, and urine by high-performance liquid chromatography. With increasing doses, the apparent elimination half-lives of TA and TASO increased linearly, indicating that TA bioactivation exhibits saturation kinetics. Increasing TA dose resulted in greater-than-proportional increases in plasma TA and TASO levels. The TASO/TA ratio was inversely proportional to the dose of TA. Covalent binding of 14 C-TA-derived radiolabel to liver macromolecules showed a lessthan-dose-proportionate increase with a 12-fold higher dose. Less than dose-proportional covalent binding was confirmed in liver microsomal incubations with 14 C-TA. Three-fold higher excretion of TASO was seen in urine at the highest dose (600 mg/kg) compared with the lowest dose (50 mg TA/kg). Incubation of TA with rat liver microsomes and purified baculovirus-expressed rat and human CYP2E1 Supersomes, over a concentration range of 0.01 to 10 mM, revealed saturation of TA conversion to TASO at and above 0.05 mM TA concentration, comparable to in vivo plasma and liver levels achieved upon administration of higher doses. Calculated K m values for TA (0.1 mM) and TASO (0.6 mM) suggest that the second step of TA bioactivation is 6-fold less efficient. Collectively, the findings indicate saturation of CYP2E1 at the first (TA to TASO) and second (TASO to TASO 2 ) steps of TA bioactivation.

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Pharmacokinetics of inhaled styrene in human volunteers

Cited by 79 publications

References 7 publications

Tissue distribution of styrene, styrene glycol and more polar styrene metabolites in the mouse.

Tissue distribution of styrene, styrene glycol and more polar styrene metabolites in the mouse.

Estimating perchlorate exposure from food and tap water based on US biomonitoring and occurrence data

Saturation Toxicokinetics of Thioacetamide: Role in Initiation of Liver Injury

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