Effect of chelating agents on biliary excretion of arsenic in perfused livers of guinea pigs pretreated with As2O3.
The effect of the dithiols British Anti-Lewisite (Bal), dimercapto-propanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA) and a new metal binding agent 2,3-bis-(acetylthio)-propanesulfonamide (BAPSA) on the biliary excretion of arsenic in perfused livers of guinea pigs pretreated with As2O3 was investigated. Guinea pigs received As2O3, 2.5 mg/kg sc twice daily for 5 consecutive days. Sixteen hours after the last dose the livers were perfused (35 ml/min) with Krebs-Henseleit buffer with glucose for 80 min. After 50 min of perfusion 0.1 mmol/L or 0.7 mmol/L BAL, DMSA, DMPS, or BAPSA were added to the perfusate and arsenic elimination in the bile and effusate was measured. The total arsenic excretion in control livers between the 50th and 80th min was 6.1% of the total arsenic liver content. After antidote addition (0.1 mmol/L) the excretion increased to 7.9% (DMSA), 9.2% (BAL), 23.9% (BAPSA), and 27.1% (DMPS), respectively. After 0.7 mmol/L of antidote the excretion of arsenic was found to be 19.3% (DMSA), 19.9% (DMSA), 24.0% (BAL), and 43.3% (BAPSA), respectively. The increase resulted mainly from increased biliary excretion. In these experiments BAPSA was significantly more effective in the overall elimination of arsenic than DMSA, DMPS, and BAL. The treatment with chelating agents may cause a substantial shift to fecal elimination by the increase in biliary excretion (BAL less than DMSA less than DMPS less than BAPSA). From the therapeutic view the shift to fecal elimination may have the advantage that the amount of the toxicant which passes the kidney is reduced and thereby also the portion which might be harmful for the organ.
Reichl
F X
FX
Walther Straub-Institut fur Pharmakologie und Toxikolog, Ludwig-Maximillans-Universitat Munchen, Federal Republic of Germany.
Kreppel
H
H
Szinicz
L
L
Muckter
H
H
Fichtl
B
B
Schumann
K
K
Forth
W
W
D000818:Animals; D001151:Arsenic / Q000493:pharmacokinetics*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001646:Bile / Q000187:drug effects* / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010087:Oxides; D010477:Perfusion; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology
D001152:Arsenicals; D002614:Chelating Agents; D010087:Oxides; D014050:Toluene; D001151:Arsenic; D000077237:Arsenic Trioxide; C004848:dithiol