Lack of correlation between in vitro and in vivo studies on the effects of tangeretin and tangerine juice on midazolam hydroxylation.
BACKGROUND
Tangeretin is a flavonoid that stimulates the catalytic activity 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 probe, was examined in vitro with human liver microsomes and recombinant CYP3A4. 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 healthy volunteers.


RESULTS
In microsomes from three human livers, tangeretin (1 to 100 micromol/L) increased 1'-hydroxymidazolam formation (12.5 micromol/L midazolam) by up to 212%. In complementary deoxyribonucleic acid-expressed CYP3A4, a 52% stimulation of midazolam 1'-hydroxylation was reached at 50 micromol/L tangeretin with no effect on midazolam 4-hydroxylation. In the pharmacokinetic-pharmacodynamic study, 200 mL tangerine juice reduced the area under the concentration versus time curve to 1.5 hours [AUC(O-1.5h)] of midazolam and 1'-hydroxymidazolam by 39% and 46%, respectively, and prolonged the time to reach peak concentration (P < .05) without affecting the total AUC values, elimination half-life values, or AUC ratios (1'-hydroxymidazolam/midazolam). These findings are consistent with a small delay in the absorption of midazolam and lack of effect on midazolam 1'-hydroxylation. Accordingly, tangerine juice slightly postponed the maximum pharmacodynamic effects of midazolam (P < .05).


CONCLUSIONS
Tangeretin is a potent regioselective stimulator of midazolam 1'-hydroxylation by human liver microsomes and complementary deoxyribonucleic acid-expressed CYP3A4. However, tangerine juice is unlikely to have any appreciable effect on CYP3A4 in humans. Further studies are required to assess whether in vitro stimulators of CYP3A4 can influence drug metabolism in vivo.
Backman
J T
JT
Department of Clinical Pharmacology, University of Helsinki, Finland. janne.backman@hus.fi
Mäenpää
J
J
Belle
D J
DJ
Wrighton
S A
SA
Kivistö
K T
KT
Neuvonen
P J
PJ
D000328:Adult; D000704:Analysis of Variance; D014151:Anti-Anxiety Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D047309:Flavones; D005419:Flavonoids / Q000494:pharmacology*; D005638:Fruit; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D000970:Antineoplastic Agents; D047309:Flavones; D005419:Flavonoids; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C059006:tangeretin; D008874:Midazolam