Different roles of pummelo furanocoumarin and cytochrome P450 3A5*3 polymorphism in the fate and action of felodipine.
OBJECTIVE
Herein we aim to test if pummelo furanocoumarins can inhibit cytochrome P450 (CYP) 3A both in vitro and in vivo, and to explore the influence of CYP3A5*3 (GenBank AC005020: A22893-->G) polymorphism in the pharmacokinetics and pharmacological response to felodipine.


METHODS
Fruit juices of pummelo grapefruit (Citrus paradisi Macf., G), 'Guanximiyou' (C. grandis Osbeck vs. Guanxi, P) and 'Changshanhuyou' (C. changshanhuyou Y.B. Chang, H) were selected by screening Citrus fruit juices for their furanocoumarin contents and their inhibition of testosterone 6beta-hydroxylation in human liver microsomes. Twelve healthy male Chinese were administered 250 mL G, P, H or water (W) alternatively with 26-mumol (10-mg) plain tablet felodipine, and were observed for 12 h.


RESULTS
G had more furanocoumarins and at higher levels than P while H had none, and their potencies for in vitro CYP3A inhibition were in the order as G > P > H. The geometric mean and 90% confidence intervals of pharmacokinetic parameters for human oral felodipine with G, P, H and W were respectively as follows: peak plasma concentration (nmol.L(-1)), 37 (32-44), 25 (21-29), 19 (16-22) and 18 (15-21); area under the plasma concentration-time curve (nmol.h.L(-1)), 118 (103-136), 84 (73-97), 64 (56-74) and 59 (51-68). Subjects showed higher heart rates with G than with H or W. CYP3A5*3 polymorphism showed no significant effect on felodipine pharmacokinetics and related hemodynamic changes.


CONCLUSIONS
This work supports the hypothesis that CYP3A inhibition by furanocoumarins caused pummelo fruit juice-drug interaction; while the role of CYP3A5 in the population pharmacokinetics of felodipine and blood pressure response appear to be limited.
Guo
Lian-Qing
LQ
Department of Pharmacology, Jinling Hospital, 305 Zhongshan East Road, Nanjing 210002, Jiangsu, P.R. China. guokaku@hotmail.com
Chen
Qiao-Yun
QY
Wang
Xuan
X
Liu
Yu-Xiu
YX
Chu
Xiao-Man
XM
Cao
Xiao-Mei
XM
Li
Jin-Heng
JH
Yamazoe
Yasushi
Y
D000328:Adult; D001628:Beverages / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002957:Citrus / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D015736:Felodipine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018565:Food-Drug Interactions; D011564:Furocoumarins / Q000737:chemistry / Q000494:pharmacology*; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D013739:Testosterone / Q000378:metabolism
D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D011564:Furocoumarins; D013739:Testosterone; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D015736:Felodipine