Walle T, Walle U K, Olanoff L S, Conradi E C
Br J Clin Pharmacol. 1986 Sep;22(3):317-23. doi: 10.1111/j.1365-2125.1986.tb02893.x.
The objective of this study was to determine the relationships between the total oral clearance of propranolol and the partial clearances through its primary metabolic pathways, i.e. glucuronidation, side-chain oxidation and ring oxidation. Seven young, white males were given single 80 mg oral doses of the drug together with tritium-labelled propranolol. Plasma propranolol was measured by GC/MS and fourteen metabolites were measured in urine by h.p.l.c. with radiometric detection. The total oral clearance of propranolol in these subjects varied about three-fold, from 27.5 to 71.4 ml min-1 kg-1. The clearance through glucuronidation was very similar in all subjects, ranging from 6.8 to 9.9 ml min-1 kg-1. The clearance through side-chain oxidation varied 2.4-fold, from 10.9 to 25.8 ml min-1 kg-1. Increased clearance through this pathway correlated with increased total oral clearance (r = 0.84; P less than 0.02). The clearance through ring oxidation varied as much as 5.6-fold, from 7.5 to 41.8 ml min-1 kg-1. Increased clearance through this pathway correlated highly with increased total oral clearance (r = 0.94; P less than 0.002). These observations indicate that the intersubject variability in the oral clearance of propranolol in young, white males is due mainly to differences in the activity of the ring oxidation pathway, to some extent in the side-chain oxidation pathway, but not to differences in the glucuronidation pathway. The partial metabolic clearance approach adopted in this study may be useful in the investigation of factors influencing the oral bioavailability of propranolol.
本研究的目的是确定普萘洛尔的口服总清除率与其主要代谢途径（即葡萄糖醛酸化、侧链氧化和环氧化）的部分清除率之间的关系。给7名年轻的白人男性单次口服80 mg该药物以及氚标记的普萘洛尔。通过气相色谱/质谱法测定血浆普萘洛尔，并通过高效液相色谱法和放射性检测法测定尿液中的14种代谢物。这些受试者中普萘洛尔的口服总清除率变化约3倍，范围为27.5至71.4 ml min⁻¹ kg⁻¹。所有受试者通过葡萄糖醛酸化的清除率非常相似，范围为6.8至9.9 ml min⁻¹ kg⁻¹。通过侧链氧化的清除率变化2.4倍，范围为10.9至25.8 ml min⁻¹ kg⁻¹。该途径清除率的增加与口服总清除率的增加相关（r = 0.84；P < 0.02）。通过环氧化的清除率变化高达5.6倍，范围为7.5至41.8 ml min⁻¹ kg⁻¹。该途径清除率的增加与口服总清除率的增加高度相关（r = 0.94；P < 0.002）。这些观察结果表明，年轻白人男性中普萘洛尔口服清除率的个体间差异主要是由于环氧化途径活性的差异，在一定程度上是由于侧链氧化途径的差异，而不是由于葡萄糖醛酸化途径的差异。本研究采用的部分代谢清除率方法可能有助于研究影响普萘洛尔口服生物利用度的因素。
