Pulmonary extraction and pharmacokinetics of prostaglandin E1 during continuous intravenous infusion in patients with adult respiratory distress syndrome.
Prostaglandin E1 (PGE1) is currently being evaluated in clinical trials to determine its usefulness in the treatment of adult respiratory distress syndrome (ARDS). The drug is administered to ARDS patients by continuous intravenous infusion at dosage rates of up to 30 ng/kg/min for 7 days. The present study was conducted to determine the pulmonary extraction efficiency and pharmacokinetics of PGE1 under these conditions. Plasma levels of PGE1 were determined by high performance liquid chromatography in 14 patients who either had ARDS or were considered to be at risk of developing ARDS following trauma or sepsis. Predose plasma levels of PGE1 were below the detection limit of the assay (50 pg/ml). At a dosage rate of 30 ng/kg/min, pulmonary arterial and systemic arterial plasma levels ranged from 265 to 1,009 pg/ml and 50 to 796 pg/ml, respectively. The pulmonary extraction ratio (Ep) of PGE1 varied from 0.11 to 0.90 and was independent of dose but dependent on cardiac output. The data were adequately described by first-order pharmacokinetic equations which assumed that the lung was the only site of PGE1 clearance. Nine of 10 patients with AaPO2/FlO2 below 510 mm Hg had Ep greater than 0.7 and high pulmonary intrinsic clearance for PGE1 (ca. 250 L/min), but all 4 patients with AaPO2/FlO2 above 510 mm Hg had Ep less than 0.6 and low intrinsic clearance (ca. 37 L/min or less). The intrinsic clearance of the lung for PGE1 in ARDS patients therefore appears to decrease abruptly once a threshold of severe respiratory failure is achieved.
Cox
J W
JW
Division of Pharmaceutical Research, Upjohn Company, Kalamazoo, Michigan 49001.
Andreadis
N A
NA
Bone
R C
RC
Maunder
R J
RJ
Pullen
R H
RH
Ursprung
J J
JJ
Vassar
M J
MJ
D000328:Adult; D000368:Aged; D000527:Alprostadil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008168:Lung / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011659:Pulmonary Gas Exchange; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology
D000527:Alprostadil