Jt. Backman et al., Lack of correlation between in vitro and in vivo studies on the effects oftangeretin and tangerine juice on midazolam hydroxylation, CLIN PHARM, 67(4), 2000, pp. 382-390
Background: Tangeretin is a flavonoid that stimulates the catalytic activit
y of cytochrome P450 3A4 (CYP3A4) and is found in high levels in tangerine
juice.
Methods: The effect of tangeretin on hydroxylation of midazolam, a CYP3A4 p
robe, was examined in vitro with human Liver microsomes and recombinant CYP
3A4, In addition, the effect of tangerine juice on the pharmacokinetics and
pharmacodynamics of orally administered midazolam (15 mg) and its active 1
'-hydroxymetabolite was studied in a randomized crossover study in eight he
althy volunteers.
Results: In microsomes from three human livers, tangeretin (1 to 100 mu mol
/L) increased 1'-hydrorymidazo-lam formation (12.5 mu mol/L midazolam) by u
p to 212%. In complementary deoxyribonucleic acid-expressed CYP3A4, a 52% s
timulation of midazolam 1'-hydroxylation was reached at 50 mu mol/L tangere
tin with no effect on midazolam 4-hydroxylation. In the pharmacokinetic-pha
rmacodynamic study 200 mL tangerine juice reduced the area under the concen
tration versus time curve to 1.5 hours [AUC(0-1.5h)] of midazo- lam and 1'-
hydroxymidazolam by 39% and 46%, respectively, and prolonged the time to re
ach peak concentration (P < .05) without affecting the total AUC values, el
imination half-life values, or AUC ratios ( 1'-hydroxymidazolam/midazolam).
These findings are consistent with a small delay in the absorption of mida
zolam and lack of effect on midazolam 1'-hydroxylation. Accordingly, tanger
ine juice slightly postponed the maximum pharmacodynamic effects of midazol
am (P < .05),
Conclusion: Tangeretin is a potent regioselective stimulator of midazolam 1
'-hydroxylation by human Liver microsomes and complementary deoxyribonuclei
c acid-expressed CYP3A4. However, tangerine juice is unlikely to have any a
ppreciable effect on CYP3A4 in humans. Further studies are required to asse
ss whether in vitro stimulators of CYP3A4 can influence drug metabolism in
vivo.