Toxicokinetics of dimethylacetamide (DMAc) in rat isolated perfused liver.
Dimethylacetamide (DMAc) is a skin-penetrating solvent able to induce hepatic damage after chronic exposure. Previous research has indicated that metabolism may be saturated at its present TLV/TWA (10 ppm). Biological monitoring of monomethylacetamide (MMAc), the primary metabolite of DMAc, might therefore underestimate exposure to DMAc and related health hazards. We used the recirculating perfusion technique in isolated rat liver to evaluate DMAc metabolism. Medium concentrations starting at about 30, 50, 100 and 275 microM, respectively, were tested. Perfusate samples were taken regularly and analysed for DMAc; pharmacokinetic parameters (extraction ratio and clearance) were calculated for each perfusion. Inlet DMAc concentrations were calculated and concentration groups divided in 16, 36, 70, 160, 225 microM. The extraction ratio of the 16 microM group differed significantly from the other concentration groups tested. DMAc metabolism was saturated at a DMAc concentration of 36 microM. Extraction ratios were unaffected when cimetidine, an inhibitor of cytochrome P450 activity, was added to the perfusion medium or when cimetidine-pretreated animals were used. DMAc clearance was 2.20 ml min-1 at a medium concentration of about 36 microM. Extrapolation of the observed (rat) liver clearance to man showed that airborne concentrations of 18 ppm would, under the presumptions used, lead to saturated metabolism of DMAc; however, saturation at even lower concentrations could not be excluded.
Palmen
N G
NG
Department of Pharmacology, University of Limburg, Maastricht, The Netherlands.
Evelo
C T
CT
Borm
P J
PJ
Henderson
P T
PT
D000081:Acetamides / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001646:Bile / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D002927:Cimetidine / Q000494:pharmacology; D003451:Cryoprotective Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000081:Acetamides; D003451:Cryoprotective Agents; D002927:Cimetidine; C013959:dimethylacetamide