Cardiac arrest and resuscitation alters the pharmacokinetics of MK-801 in the rat.
We investigated the effects of cardiac arrest and resuscitation on (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine meleate (MK-801) pharmacokinetics. The clearance of MK-801 in control animals was 108 +/- 9 mL.kg.min while its apparent volume of distribution was 12.6 +/- 0.7 L/kg. The half-life of the distribution phase was 4.9 +/- 1.2 min while that of the elimination phase was 87 +/- 8 min. Transient circulatory arrest decreased the overall clearance of MK-801 by 38% with no effect on the apparent volume of distribution. The distribution half-life was not affected although the initial distribution was increased 46%; the half-life of elimination was increased by 58%. Serum levels of transaminases in arrested animals were significantly elevated (258-322%) while blood urea nitrogen, creatinine, and creatine kinase were minimally affected, suggesting that the reduced clearance of MK-801 might be secondary to hepatic ischemic damage. Post-ischemic alterations in hemodynamics resulting in lowering and/or redistribution of cardiac output may also be responsible for the reduced clearance of MK-801 as the hemodynamic response to MK-801 in the post-ischemic animals was quite different from that in the controls. We conclude that transient cardiac arrest significantly alters the pharmacokinetics of MK-801 and that this must be taken into consideration when using this or other drugs to treat ischemic injury.
Schwartz
P H
PH
Neurology Service, Veterans Administration Medical Center, Sepulveda, California 91343.
Wasterlain
C G
CG
D000818:Animals; D001806:Blood Urea Nitrogen; D016887:Cardiopulmonary Resuscitation; D003327:Coronary Disease / Q000378:metabolism*; D003402:Creatine Kinase / Q000097:blood; D003404:Creatinine / Q000097:blood; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics*; D006207:Half-Life; D006323:Heart Arrest / Q000378:metabolism*; D006439:Hemodynamics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D000637:Transaminases / Q000097:blood
D016291:Dizocilpine Maleate; D003404:Creatinine; D000637:Transaminases; D003402:Creatine Kinase