Silber B, Holford N H, Riegelman S
J Pharm Sci. 1982 Jun;71(6):699-704. doi: 10.1002/jps.2600710623.
Following oral dosing to steady state, the disposition of S(-)- and R(+)-propranolol and their corresponding glucuronide conjugates was studied in 4 healthy adults using doses from 40 to 320 mg/day of the racemate. Steady -state plasma concentrations of S(-)-propranolol and its corresponding glucuronide conjugate were greater than that for R(+)-propranolol and its corresponding conjugate. The average steady-state concentration of both enantiomers increased disproportionately to dose. There was a 52+/- 7 (mean +/- SD) % decrease in the intrinsic clearance (clint) of S(-)-propranolol and a 65 +/- 22% decrease in the Clint of R(+)-propranolol over the dosing range studied. The terminal elimination half-lives of S(-)-propranolol and its glucuronide conjugate were longer than for the R(+)-enantiomer at all doses. The formation of glucuzonide conjugates of S(-)- and R(+)-propranolol was best described by a saturable process in all subjects. Within individuals, the ratio of Vmax/Km for the glucuronide conjugate of S(-)-propranolol was from 2.1-to 4.9-fold greater than for the conjugate of the R(+)-enantiomer. These studies demonstrate for the first time, that propranolol undergoes stereoselective disposition in humans.
在4名健康成年人中，口服消旋普萘洛尔至稳态后，使用40至320mg/天的剂量研究了S(-)-和R(+)-普萘洛尔及其相应的葡萄糖醛酸结合物的处置情况。S(-)-普萘洛尔及其相应的葡萄糖醛酸结合物的稳态血浆浓度高于R(+)-普萘洛尔及其相应结合物。两种对映体的平均稳态浓度随剂量增加的比例不成正比。在所研究的给药范围内，S(-)-普萘洛尔的内在清除率（clint）平均降低了52±7（平均值±标准差）%，R(+)-普萘洛尔的clint平均降低了65±22%。在所有剂量下，S(-)-普萘洛尔及其葡萄糖醛酸结合物的终末消除半衰期均长于R(+)-对映体。在所有受试者中，S(-)-和R(+)-普萘洛尔的葡萄糖醛酸结合物的形成最适合用饱和过程来描述。在个体内，S(-)-普萘洛尔葡萄糖醛酸结合物的Vmax/Km比值比对映体R(+)结合物的比值高2.1至4.9倍。这些研究首次证明，普萘洛尔在人体内存在立体选择性处置。
