Inhibitory Effects of Pomelo on the Metabolism of Tacrolimus and the Activities of Cyp3a4 and P-Glycoprotein

Abstract

ABSTRACT:We recently reported a case of increase in the blood level of tacrolimus following intake of pomelo in a renal transplant recipient. To clarify the mechanism of this increase in the blood level of tacrolimus, we investigated the effect of pomelo juice extract on the activities of CYP3A4 and P-glycoprotein, in comparison with that of extract of grapefruit juice (GFJ). The 10% ethyl acetate extracts of the juice of three pomelos of different origins (Banpeiyu, pomelo I; Hirado Buntan, pomelo II; and Tosa Buntan, pomelo III) and GFJ significantly inhibited 6␤-hydroxylation of testosterone in human liver microsomes by 76.4, 67.2, 37.5, and 83.9%, respectively. The extract of pomelo I was as potent as that of GFJ. The metabolism of tacrolimus itself was also inhibited by the extract of pomelo I, as well as that of GFJ. Furthermore, the inhibition of both 6␤-hydroxylation of testosterone and metabolism of tacrolimus by pomelo I and GFJ was preincubation time-dependent. On the other hand, the extract of pomelo I had little effect on the transcellular transport of tacrolimus or [ 3 H]digoxin across a monolayer of LLC-GA5-COL150 cells (a porcine kidney epithelial cell line, LLC-PK1, transfected with human MDR1 cDNA and overexpressing human P-glycoprotein). In conclusion, pomelo constituents inhibit the activity of CYP3A4 and may thereby produce an increase in the blood level of tacrolimus.

In Vivo to In Vitro Effects of Six Bioactive Lignans of Wuzhi Tablet (Schisandra Sphenanthera Extract) on the CYP3A/P-glycoprotein–Mediated Absorption and Metabolism of Tacrolimus

“…It was reported that FK506 competitively inhibited CYP3A in human liver microsomes, showing inhibition constants (Ki) of 0.61 mM (Amundsen et al, 2012). Third, the reported concentration of FK506 used in a liver-microsome-based metabolism study of FK506 was 3 ng/ml (Egashira et al, 2004). Thus, to mimic the clinical herb-drug interaction between WZ and FK506, 5 ng/ml of FK506 was chosen in the metabolism study.…”

“…In clinical practice, the recommended oral dose of FK506 is 0.15-0.3 mg/kg twice a day for renal transplant patients. Thus, for a 70-kg subject, taking the volume of the gastrointestinal tract (3-5 l) into consideration (Egashira et al, 2004), the concentration of FK506 in the intestinal surface would be 1-3.5 mg/ml. In addition, a previous study (Pawarode et al, 2007) showed that 1 mM (about 0.8 mg/ml) of FK506 could enhance cellular drug uptake in cells overexpressing P-gp, multidrug resistance-associated protein 1 (MRP-1), or Breast cancer resistance-related protein (BCRP).…”

The Inhibitory Effect of Cranberry Juice on Phenytoin Metabolism by Human Liver Microsomes

“…આ．Influence of CrJ on the metabolism of PHT by human liver microsomes Human liver microsome assay was performed according to the previous report with a minor modification 9) . In brief, 280 mL of reaction mixture was pre-incubated for 10 min at 37℃ by addition of human ／ liver microsomes（final concentration；0.48 mg／mL） to the NADPH-regenerating system（1.3 mM NADP, ／ 3.3 mM glucose 6-phosphate, 0.4 U／mL glucose-6-phosphate dehydrogenase, 3.3 mM MgCl2）in 50 mM phosphate buffer（pH7.4）with 10 mL of CrJ extract （final extract concentration；0.3 and 1％）or SFZ solution（final concentration；0.3 and 1.0 mM).…”

“…Preparation of the cranberry juice（CrJ）extract was performed according to the method reported previously 9) . CrJ was mixed with 3-fold volumes of ethyl acetate and shaken vigorously for 20 min, and the mixture was centrifuged at 900 g for 10 min.…”

Transient Inhibition of Cyp3a in Rats by Star Fruit Juice

“…The mechanism of this interaction involves reversible or irreversible (mechanism-based) inhibition of CYP3A4 in the small intestine (Bailey et al, 2000). In addition, recent reports have indicated that various types of fruits, including those of the citrus species, have an inhibitory effect on CYP3A activities in the liver and gut wall and thereby alter the pharmacokinetics of certain drugs (Di Marco et al, 2002;Bailey et al, 2003;Egashira et al, 2004;von Moltke et al, 2004).…”