Pomegranate juice does not impair clearance of oral or intravenous midazolam, a probe for cytochrome P450-3A activity: comparison with grapefruit juice.
The effect of pomegranate juice (PJ) or grapefruit juice (GFJ) on CYP3A activity was studied in vitro and in healthy human volunteers. In human liver microsomes, the mean 50% inhibitory concentrations (IC(50)) for PJ and GFJ versus CYP3A (triazolam alpha-hydroxylation) were 0.61% and 0.55%, (v/v) respectively, without preincubation of inhibitor with microsomes. After preincubation, the IC(50) for PJ increased to 0.97% (P < .05), whereas the IC(50) for GFJ decreased to 0.41% (P < .05), suggesting mechanism-based inhibition by GFJ but not PJ. Pretreatment of volunteer subjects (n = 13) with PJ (8 oz) did not alter the elimination half-life, volume of distribution, or clearance of intravenous midazolam (2 mg). Administration of PJ also did not affect C(max), total area under the curve (AUC), or clearance of oral midazolam (6 mg). However, GFJ (8 oz) increased midazolam C(max) and AUC by a factor of 1.3 and 1.5, respectively, and reduced oral clearance to 72% of control values. Thus, PJ does not alter clearance of intravenous or oral midazolam, whereas GFJ impairs clearance and elevates plasma levels of oral midazolam.
Farkas
Dora
D
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
Oleson
Lauren E
LE
Zhao
Yanli
Y
Harmatz
Jerold S
JS
Zinny
Miguel A
MA
Court
Michael H
MH
Greenblatt
David J
DJ
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001628:Beverages; D032083:Citrus paradisi / Q000737:chemistry*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D018565:Food-Drug Interactions; D018757:GABA Modulators / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007275:Injections, Intravenous; D029561:Lythraceae / Q000737:chemistry*; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D014229:Triazolam / Q000031:analogs & derivatives / Q000378:metabolism
D018757:GABA Modulators; D014229:Triazolam; C028638:alpha-hydroxytriazolam; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam