TY - JOUR
T1 - Uptake and elution of chlormethiazole, meperidine, and minaxolone in the hindquarters of sheep
T2 - Implications for clearance calculations
AU - Upton, R. N.
AU - Mather, L. E.
AU - Runciman, W. B.
AU - McLean, C. F.
AU - Carapetis, R. J.
PY - 1991
Y1 - 1991
N2 - Mass balance principles were used to describe the uptake and elution of chlormethiazole, meperidine, and minaxolone in the hindquarters of sheep. Sheep received a right atrial infusion of either chlormethiazole (3.71 mg/min) or meperidine (2.70 mg/min) for 180 min, or minaxolone (0.37 mg/min) for 120 min. Paired arterial and inferior vena cava (draining the hindquarters) blood samples were taken during and after the infusion. The mean and SD (n = 4) of the time‐averaged extraction ratios across the hindquarters (determined from the relevant arterio‐venous area under blood concentration—time curves) were 0.12 (0.10), 0.36 (0.13), and 0.27 (0.05) for chlormethiazole, meperidine, and minaxolone, respectively. The rank order of the rate of uptake of the drugs into the hindquarters was the same as the rank order of their lipophilicity, and uptake still continued when both the arterial and inferior vena cava drug concentrations were essentially constant. For chlormethiazole, meperidine, and minaxolone, 48% (44), 4% (6), and 35% (17), respectively, of the drug taken into the hindquarters eluted from the hindquarters after the infusion. Drug uptake and retention in extravisceral tissues, represented here by the hindquarters, can result in the mean total body drug clearance being overestimated when determined by traditional systemic pharmacokinetic methods.
AB - Mass balance principles were used to describe the uptake and elution of chlormethiazole, meperidine, and minaxolone in the hindquarters of sheep. Sheep received a right atrial infusion of either chlormethiazole (3.71 mg/min) or meperidine (2.70 mg/min) for 180 min, or minaxolone (0.37 mg/min) for 120 min. Paired arterial and inferior vena cava (draining the hindquarters) blood samples were taken during and after the infusion. The mean and SD (n = 4) of the time‐averaged extraction ratios across the hindquarters (determined from the relevant arterio‐venous area under blood concentration—time curves) were 0.12 (0.10), 0.36 (0.13), and 0.27 (0.05) for chlormethiazole, meperidine, and minaxolone, respectively. The rank order of the rate of uptake of the drugs into the hindquarters was the same as the rank order of their lipophilicity, and uptake still continued when both the arterial and inferior vena cava drug concentrations were essentially constant. For chlormethiazole, meperidine, and minaxolone, 48% (44), 4% (6), and 35% (17), respectively, of the drug taken into the hindquarters eluted from the hindquarters after the infusion. Drug uptake and retention in extravisceral tissues, represented here by the hindquarters, can result in the mean total body drug clearance being overestimated when determined by traditional systemic pharmacokinetic methods.
UR - http://www.scopus.com/inward/record.url?scp=0026078092&partnerID=8YFLogxK
U2 - 10.1002/jps.2600800204
DO - 10.1002/jps.2600800204
M3 - Article
C2 - 2051311
AN - SCOPUS:0026078092
SN - 0022-3549
VL - 80
SP - 108
EP - 112
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 2
ER -