Circulating metabolites of Borneolum syntheticum (Bingpian) inhibit foam-cell formation in macrophages induced by oxidized low-density lipoprotein

Coronary heart disease is caused by the accumulation of atherosclerotic plaques which narrow the arteries over time. The plaques are formed by cholesterol deposits in the arterial intima and lead to the symptom of angina pectoris. Borneolum syntheticum (Bingpian) has been extensively used as a component in Chinese herbal medicines for cardiovascular diseases. This investigation aimed to examine Bingpian metabolism and its effects on anti-atherosclerotic activities. Major circulating Bingpian compounds were detected in human subjects who received a Bingpian-containing medicine. In vitro and rat studies were also conducted to facilitate the understanding of disposition factors that govern the systemic exposure to Bingpian compounds. Although Bingpian constituents, borneol (1) and isoborneol (2), are efficiently absorbed in the intestine, extensive hepatic first-pass glucuronidation, which is mediated predominantly by UGT2B7, coupled with MRP3 and MRP4-mediated efflux of the glucuronides into the blood, and oxidation, which is mediated by CYP2A6, CYP2B6, and CYP3A, result in the formation of metabolites borneol-2-O-glucuronide (M1G), isoborneol-2-O-glucuronide (M2G), and camphor (3) as the major circulating Bingpian compounds instead of the unchanged 1 and 2. Glucuronides are predominantly eliminated through renal excretion, which involves both glomerular filtration and OAT3- and OAT4-mediated tubular secretion. Furthermore, M1G, M2G, and 3, as well as 1 and 2, displayed inhibitory effects on oxidized low-density lipoprotein-induced foam-cell formation in macrophages. The findings emphasized that the metabolites must be given priority in pharmacodynamic studies of Bingpian. Comprehensive integration of pharmacokinetic and pharmacodynamic studies facilitates understanding how Bingpian functions in the body to provide therapeutic benefits.