title: In vivo and in vitro characterization of ethyl methanesulfonate pharmacokinetics in animals and in human.
abstract: Pharmacokinetics of ethyl methanesulfonate (EMS) were characterized in mice, rats and in cynomolgus monkeys with unlabelled and (14)C-radiolabelled EMS by either quantification of unchanged EMS or the N-ethyl-valine haemoglobin (Hb) adduct. EMS was well absorbed and exhibited close to 100% oral bioavailability. EMS showed some species differences in systemic clearance (intermediate in mice, low in rats and monkeys) representing only 1-4% of the cardiac output. The volume of distribution (0.5-0.8L/kg) was constant across species and corresponded to extracellular water. As a result of the species differences in clearance, the half-life ranged from 10 min in mouse (at low dose) to 5h in monkey. The systemic exposure of free EMS and the levels of its Hb adduct increased nearly dose proportionately from 1 to 5 and 0.5 to 80 mg/kg, respectively. The persistence of the N-ethyl-valine Hb adduct was much longer than EMS itself, consistent with the long life span of haemoglobin. No species differences were evident for the binding of EMS to Hb in whole blood ex vivo as determined by the second order rate constants. Following administration of Viracept tablets of the contaminated production batches (to monkeys leading to EMS doses of 0.08-27 microg/kg, concentrations of ethyl-valine Hb adducts) were near or below the detection limit of the assay (0.043 nmol/g Hb).
authors.affiliation: Drug Metabolism and Pharmacokinetics Department, F. Hoffmann-La Roche Ltd., Basel, Switzerland. thierry.lave@roche.com
authors.forename: Thierry
authors.initials: T
authors.lastname: Lavé
authors.forename: Herbert
authors.initials: H
authors.lastname: Birnböck
authors.forename: Andreas
authors.initials: A
authors.lastname: Götschi
authors.forename: Thomas
authors.initials: T
authors.lastname: Ramp
authors.forename: Axel
authors.initials: A
authors.lastname: Pähler
mesh_terms: D000477:Alkylating Agents / Q000493:pharmacokinetics*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004340:Drug Contamination; D005020:Ethyl Methanesulfonate / Q000493:pharmacokinetics*; D017320:HIV Protease Inhibitors / Q000737:chemistry; D006207:Half-Life; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009153:Mutagens / Q000493:pharmacokinetics*; D019888:Nelfinavir / Q000737:chemistry; D051381:Rats; D018570:Risk Assessment; D013045:Species Specificity; D013607:Tablets; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D017320:HIV Protease Inhibitors; D006454:Hemoglobins; D009153:Mutagens; D013607:Tablets; D005020:Ethyl Methanesulfonate; D014633:Valine; D019888:Nelfinavir