Pharmacokinetics and acute cardiovascular effects of menogaril in patients with metastatic tumors.
The new anthracyclin, menogaril [7-(R)-0-methylnogarol], is reported to produce less cardiotoxicity than doxorubicin after multiple doses. This study was designed to assess acute hemodynamic changes during the first administration of menogaril and to relate these changes to plasma concentrations. Menogaril (200 mg/mg) was infused over 90 minutes to 4 patients with metastatic colon or prostate cancer. Cardiac output (CO) and stroke volume (SV) were measured noninvasively by Doppler ultrasound. Menogaril plasma concentrations were measured by HPLC and a 3-compartment mammillary model was used for pharmacokinetic analysis of the results. Steady-state volume of distribution, elimination clearance, and elimination half-life averaged 1,114 +/- 340 l/m2, 38 +/- 16 l/h/m2 and 40.3 +/- 30.3 hours, respectively. All patients were normotensive (baseline blood pressure = 135 +/- 10/73.5 +/- 8 mmHg) and ejection fractions were in normal range (EF = 68 +/- 7%). Transient increase in mean arterial pressure (MAP) from 93 +/- 3 to 107 +/- 4 mmHg (p < or = 0.001) were seen during and shortly after the end of menogaril infusion in all patients. Heart rate (78 +/- 5 min-1) remained constant. CO fell slightly and total peripheral resistance (TPR) increased by 36.8% in the last 2 patients. The increase in MAP was analyzed by a linear-effect model and averaged 0.028 +/- 0.017 mmHg per ng/ml of menogaril in the hypothetical biophase. The half-life for menogaril equilibration between plasma and this biophase was 41 +/- 22 minutes. We conclude that during acute administration of menogaril, blood pressure increases transiently secondary to an increase in TPR.(ABSTRACT TRUNCATED AT 250 WORDS)
Piergies
A A
AA
Department of Medicine, Evanston Hospital, Illinois, USA.
Benson
A B
AB
D000368:Aged; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D017290:Menogaril / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D014655:Vascular Resistance / Q000187:drug effects
D017290:Menogaril