Lankford S M, Maskasame C, Bai S A
Department of Anatomy, Physiological Sciences, and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh 27606.
Drug Metab Dispos. 1994 Sep-Oct;22(5):776-87.
The intravenous and oral dose kinetics and metabolism of the enantiomers of propranolol were investigated in five dogs during steady-state oral racemic propranolol dosing (5 mg/kg, every 8 hr for 3 days). These results were compared with those obtained during concomitant administration of oral diltiazem (2.5 mg/kg, every 8 hr for 3 days) in the same animals. The oral and intravenous propranolol test doses consisted of a pseudoracemic mixture of equal amounts of hexadeuterated-(R-(+))- and dideuterated-(S-(-))-propranolol. Propranolol metabolism in the urine was evaluated by coadministering 150 muCi of [4'-3H]racemic propranolol HCl, along with the deuterium-labeled compounds. Plasma concentrations of the deuterated enantiomers were measured by HPLC-thermospray MS, using undecadeuterated racemic propranolol as the internal standard. Diltiazem coadministration had no significant effects on either the systemic clearance, renal clearance, the apparent volume of distribution, or the elimination half-lives of either enantiomer. On the other hand, concomitant diltiazem treatment significantly reduced the oral clearance of S-(-)- and R-(+)-propranolol by 58 and 61%, respectively. These reductions resulted in an increase in their respective apparent steady-state oral availabilities of 129 and 106%. The S/R enantiomeric ratio of the oral availability of propranolol was not significantly changed from control. The urinary propranolol metabolites were isolated and purified by solvent extraction and HPLC and quantitated by radioactivity. Twelve metabolites, including propranolol, were isolated and quantitated in the urine. A significant reduction in the percentage of ring oxidation products and a significant increase in the percentage of naphthoxylactic acid and propranolol glucuronide excreted in the urine occurred in the diltiazem-treated animals. The S/R enantiomeric ratios of urinary excreted propranolol, propranolol glucuronide, 4'-hydroxypropranolol glucuronide, and its sulfate were not altered by diltiazem. These results suggest that the decreased oral clearances of the enantiomers of propranolol by diltiazem is caused by a selective decrease in the formation of ring-oxidized products.
在五只犬中，在口服消旋普萘洛尔达到稳态给药（5mg/kg，每8小时一次，共3天）期间，研究了普萘洛尔对映体的静脉内和口服剂量动力学及代谢情况。将这些结果与同一批动物在同时给予口服地尔硫䓬（2.5mg/kg，每8小时一次，共3天）时获得的结果进行比较。口服和静脉内给予的普萘洛尔试验剂量由等量的十六氘代 - (R-(+)) - 和二氘代 - (S-(-)) - 普萘洛尔的假消旋混合物组成。通过同时给予150μCi的[4'-³H]消旋普萘洛尔盐酸盐以及氘标记化合物来评估尿液中的普萘洛尔代谢情况。使用十一氘代消旋普萘洛尔作为内标，通过HPLC - 热喷雾质谱法测量氘代对映体的血浆浓度。同时给予地尔硫䓬对任何一种对映体的全身清除率、肾清除率、表观分布容积或消除半衰期均无显著影响。另一方面，同时给予地尔硫䓬治疗分别使S-(-)-和R-(+)-普萘洛尔的口服清除率显著降低了58%和61%。这些降低导致它们各自表观稳态口服生物利用度分别增加了129%和106%。普萘洛尔口服生物利用度的S/R对映体比率与对照组相比无显著变化。通过溶剂萃取和HPLC分离并纯化尿液中的普萘洛尔代谢产物，并通过放射性进行定量。在尿液中分离并定量了包括普萘洛尔在内的12种代谢产物。在接受地尔硫䓬治疗的动物中，尿液中排出的环氧化产物百分比显著降低，萘氧基乳酸和普萘洛尔葡萄糖醛酸苷的百分比显著增加。地尔硫䓬未改变尿液中排出的普萘洛尔、普萘洛尔葡萄糖醛酸苷、4'-羟基普萘洛尔葡萄糖醛酸苷及其硫酸盐的S/R对映体比率。这些结果表明，地尔硫䓬导致普萘洛尔对映体口服清除率降低是由于环氧化产物形成的选择性减少所致。
