Relationship between serum concentrations, hemodynamic effects, and cardiovascular lesions in dogs treated with minoxidil.
The threshold hemodynamic changes associated with the cardiovascular (CV) toxicity of minoxidil (MNX) in the dog, characterized by subendocardial necrosis, right atrial hemorrhagic lesions, and coronary vascular medial hemorrhage and necrosis, have not been defined. To determine the relationship between serum concentration, hemodynamic effects [heart rate (HR) and mean arterial pressure (MAP)] and CV toxicity, groups of female Beagle dogs were treated with a continuous iv infusion of dextrose (control) or 0.05, 0.14, 0.43, 1.44, or 4.32 mg/kg/day of MNX for 3 days. Serum concentration of free MNX increased in a dose-related manner and reached steady state within 4 hr after the initiation of infusion. There was a time-dependent, apparently dose-related increase in HR at all doses. MAP was decreased at > or = 0.14 mg/kg/day in a time- and dose-related manner. The doses or steady-state serum concentrations of MNX that showed no significant hemodynamic effects and CV toxicity were approximately 0.05 mg/kg or 3.0 +/- 0.6 ng/ml and 0.14 mg/kg or 7.3 +/- 2.0 ng/ ml, respectively. CV toxicity occurred at a serum concentration of 16.6 +/- 1.9 ng/ml where HR was increased by 65 +/- 11 beats/min and MAP was decreased by 34 +/- 2 mm Hg. A serum concentration of 7.3 +/- 2 ng/ml of MNX that increased HR by 47 +/- 14 beats/min and decreased MAP by 17 +/- 8 mm Hg was not associated with CV toxicity. This study suggests that the threshold hemodynamic effects associated with the CV toxicity of MNX in the dog are a function of an increase in HR by at least 55 beats/min and a decrease in MAP by at least 30 mm Hg. In conclusion, the safety margin of drugs like MNX, where the mechanisms of toxicity are known to be related to their pharmacologic effects, should be based on the ratio of the pharmacokinetically and metabolically adjusted dose/serum concentration of the drug that evokes comparable pharmacologic effects in the animal model and humans rather than on the ratio of the nontoxic dose/serum concentration in animals to the efficacious dose in humans.
Pharmacia & Upjohn Inc., Worldwide Drug Safety, Kalamazoo, Michigan 49001, USA.
G M
GM
Mesfin
M J
MJ
Higgins
F G
FG
Robinson
W Z
WZ
Zhong
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003327:Coronary Disease / Q000139:chemically induced / Q000473:pathology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008914:Minoxidil / Q000009:adverse effects* / Q000097:blood* / Q000493:pharmacokinetics
D008914:Minoxidil