ABSTRACT
Furanocoumarin derivatives, known as components of grapefruit juice, showing inhibitory effects against P-glycoprotein (P-gp) in the intestine are also contained in the plants of rutaceae and umbelliferae families, which are used as components of Kampo extract medicines. In this study, we investigated the inhibitory effects of byakangelicol and rivulobirin A, known as furanocoumarins showing P-gp inhibitory effect using Caco-2 monolayer, against P-gp at the blood-brain barrier (BBB) under both in vitro and in vivo conditions. First we studied the membrane permeability of furanocoumarins to clarify whether they can be absorbed from the intestine. Both furanocoumarins showed high permeability through the Caco-2 monolayer, suggesting that they can easily reach the systemic circulation after oral administration. Then, we evaluated the effect of these furanocoumarins on the uptake of calcein acetoxymethyl ester (calcein-AM), a P-gp substrate, into bovine brain microvascular endothelial cells (BBMEC). Both furanocoumarins significantly increased the uptake amount of calcein-AM into BBMEC by the inhibition of P-gp at the BBB in vitro. Next we also investigated the P-gp inhibitory effect of these furanocoumarins at the rat BBB in vivo using verapamil as a P-gp substrate. Both furanocoumarins increased the B/P ratio of verapamil compared to the control, even under in vivo conditions; however, the extent of the inhibitory effect was much lower than in vitro condition. In conclusion, byakangelicol and rivulobirin A may inhibit P-gp expressed at the BBB even under in vivo conditions. Further studies using Kampo extract medicines under in vivo condition are necessary for safe drug therapy.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Blood-Brain Barrier/drug effects , Coumarins/pharmacology , Enzyme Inhibitors/pharmacology , Furans/pharmacology , Furocoumarins/pharmacology , Herb-Drug Interactions , Plant Extracts/pharmacology , Animals , Apiaceae/chemistry , Biological Transport/drug effects , Blood-Brain Barrier/cytology , Blood-Brain Barrier/metabolism , Caco-2 Cells , Cattle , Citrus paradisi/chemistry , Coumarins/pharmacokinetics , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Enzyme Inhibitors/pharmacokinetics , Fluoresceins/metabolism , Furans/pharmacokinetics , Furocoumarins/pharmacokinetics , Humans , Intestinal Absorption , Male , Medicine, Kampo , Permeability , Plant Extracts/chemistry , Plant Extracts/pharmacokinetics , Rats , Rats, Wistar , Rutaceae/chemistry , Verapamil/metabolismABSTRACT
Furanocoumarins in grapefruit are known to show inhibitory effects against P-glycoprotein (P-gp) and CYP3A4 in intestinal epithelial cells; however, furanocoumarin derivatives are widely contained in the plants of Rutaceae and Umbelliferae families, which are used as components of Kampo extract medicines. In this study, we investigated the inhibitory effects of 12 furanocoumarins extracted from plants in the Umbelliferae family against P-gp and CYP3A4 activity. Furthermore, we studied their inhibitory effect on P-gp when furanocoumarins are used as Kampo extract medicine rather than as an isolated single compound. From screening of the CYP3A4 inhibitory effect, notopterol and rivulobirin A, the only dimer types of furanocoumarin, were found to be potent inhibitors of CYP3A4. On the other hand, byakangelicol and rivulobirin A showed strong P-gp inhibition from the screening of P-gp inhibitor evaluated by quinidine permeation through the Caco-2 monolayer; however, the chemical structural relationship of furanocoumarins between P-gp and CYP3A4 inhibitory effects could not be obtained. We also investigated the effect of these furanocoumarins on the transport of digoxin through the Caco-2 monolayer. The inhibitory effect of rivulobirin A was more potent than that of byakangelicol. Application of either Senkyu-cha-cho-san or Sokei-kakketsu-to, which are composed of herbal remedies in the Umbelliferae group, significantly decreased the efflux ratio of digoxin. In conclusion, it was found that some furanocoumarins extracted from the plants in the Umbelliferae family strongly inhibited P-gp and CYP3A4. Kampo extract medicines containing herbal remedies belonging to the Umbelliferae family may cause a drug-drug interaction with P-gp or a CYP3A4 substrate drug.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Cytochrome P-450 CYP3A Inhibitors , Furocoumarins/pharmacology , Medicine, Kampo , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Anti-Arrhythmia Agents/metabolism , Caco-2 Cells , Cytochrome P-450 CYP3A/metabolism , Digoxin/metabolism , Furocoumarins/metabolism , Humans , Midazolam/analogs & derivatives , Midazolam/metabolism , Quinidine/metabolismABSTRACT
Access to drug information (DI) needed to evaluate generic product bioequivalence was studied to identify problems with the current status of DI availability and encourage proper use of DI. Ten items were chosen from among the stock of branded products at the University Pharmacy, and five corresponding generics were selected for each item. Conditions of access to information on pharmacokinetic tests and dissolution tests were rated and the assigned ratings compared. In the case of pharmacokinetic parameters obtainable from makers of generic drugs, we also performed Welch's t-test to compare the difference between values reported for branded and generic products. From the standpoint of individual tests, the pharmacokinetic tests yielded higher scores on the whole than did the dissolution tests, and low scores were obtained for the half-life of blood drug concentration (T1/2). We observed a tendency for the adequacy of information to depend more upon the drug item itself than upon the nature of the test. The percentage of tests allowing for comparison with branded products varied from 0%-75% (average 49%). Parameter by parameter, the range of variation was from 35% of Tmax to 63% of Cmax. Factors precluding comparison included insufficient data on branded products, mismatch in assayed chemical species between branded and generic, mismatch between final sampling time in AUC(t) measurement, dosage inconsistency, and insufficient data on generic products. DI should be provided in a manner that facilitates comparison of information supplied by generic drug makers with data released by makers of branded products.