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Introduction
Osthole [7-methoxy-8-(3-methyplent-2-enyl) coumarin; Fig. 1A], a poorly water-soluble natural coumarin, is the main active component of the Fructus Cnidii and Heracleum moellendorffii Hance plant species. Osthole has been confirmed to possess numerous beneficial bioactivities including anti-inflammatory (1), neuroprotection (2) and antiosteoporotic activities (3). In addition, osthole has beneficial effects in glioblastoma multiforme (4), diabetes and acute ischemic stroke (5,6). Although osthole possesses many biological and pharmacological activities, the application of osthole in the clinic has been limited due to its poor bioavailability and low plasma concentration (7,8), which results from rapid elimination by the CYP3A4 enzyme in the liver (9). In addition, osthole is excreted in the kidneys and bile, which rely on the excretory function of P-glycoprotein (10).
Borneol, which is widely used in herbal medicine, is a component in the essential oils of numerous spice berries including Lavandula, Thymus vulgaris and Rosmarinus officinalis Linnaeus (11–13). In the molecular structure of borneol there is one chiral carbon atom, which produces two optical isomers: (+)-Borneol and (−)-borneol (Fig. 1B). Synthetic borneol [a racemate composed of (+)- and (−)-borneol, isoborneol (Fig. 1A)] is increasingly being applied to replace (+)- and (−)-borneol as there is an unlimited source and it is relatively inexpensive. Borneol has additionally been used as a Chinese medicine exhibiting various bioactivities including sedation, anti-inflammation and antioxidant activity (14–16). Notably, according to Chinese medicine, borneol was considered as a ‘guide’ drug, regulating and mediating the delivery of other prescription drugs (17). Previous studies have confirmed that borneol enhances the bioavailability of other drugs through pharmacokinetic interactions, including the intestinal absorption of salvianolic acid B and Akebia saponin (18,19), the distribution of danshensu to the eye (20) and nasal absorption of geniposide (21). Previous studies have identified the differences between (+)- and (−)-borneol in their interactions with cytochrome P450 enzyme and p-glycoprotein, which serve an important role in the absorption and elimination of drugs (22–24). These studies indicated that there may be differences between the pharmacokinetic interactions of (+)- and (−)-borneol. In traditional Chinese medicine, co-administration of borneol with herbal drugs containing osthole, including Angelica pubescens, Fructus cnidii and Libanotis buchtormensis (Fisch.) DC, was commonly used (25). In addition, borneol inhibits cytochrome P450 enzyme, which participates in the elimination of osthole...