Isoxanthohumol, a hop-derived flavonoid, alters the metabolomics profile of mouse feces.

The aim of this study was to verify the effect of treatment with isoxanthohumol (IX) on the metabolomics profile of mouse feces to explore the host-intestinal bacterial interactions at the molecular level. The fecal contents of several amino acids in the high-fat diet (HFD) + 0.1% IX group (treated with IX mixed in diets for 12 weeks) were significantly lower than in the HFD group. The fecal contents of the secondary bile acid deoxycholic acid (DCA) in the HFD + 180 mg/kg IX group (orally treated with IX for 8 weeks) were significantly lower than in the HFD group; the values in the HFD group were higher than those in the normal diet (ND) group. Administration of IX changed the fecal metabolomics profile. For some metabolites, IX normalized HFD-induced fluctuations.

Anti-obesity effect of a hop-derived prenylflavonoid isoxanthohumol in a high-fat diet-induced obese mouse model.

We examined whether oral administration of a hop-derived prenylflavonoid isoxanthohumol (IX) would show anti-obesity activity and the underlying mechanism of the potential activity using a high-fat diet (HFD)-induced obese mouse model. Oral administration of 180 mg/kg IX for 8 weeks suppressed HFD-induced accumulation of visceral fat and body weight gain in mice. Simultaneously, IX changed the composition of the microbiome, as determined by a significant increase in the relative abundances of Akkermansia muciniphila, Blautia, and Escherichia coli. A. muciniphila accounted for 23% and 24% of the total microbiome in the HFD+60 mg/kg and 180 mg/kg IX groups, respectively, while it was undetectable in the normal diet (ND) and HFD groups. Similarly, Blautia accounted for 8% and 10% of the total microbiome in the HFD+60 mg/kg and 180 mg/kg IX groups, respectively, while it accounted for less than 1% in the ND and HFD groups. In contrast, a significant decrease in the relative abundance of Oscillospira was observed in the HFD+60 mg/kg and 180 mg/kg IX groups compared with the HFD group. We further examined the anti-obesity effect of IX using a germ-free (GF) mouse model to clarify the relationship between the microbiome and the effect of IX. IX showed no significant anti-obesity effect on fat accumulation and weight gain in GF mice. These results suggest that the anti-obesity effect of IX may involve microbial changes.

Microdosing clinical study to clarify pharmacokinetic and pharmacogenetic characteristics of atorvastatin in Japanese hypercholesterolemic patients.

The present study investigated whether the clinical pharmacokinetics of atorvastatin can be predicted from the results of microdosing study in Japanese patients with hypercholesterolemia whose SLCO1B1 and ABCG2 polymorphisms were analyzed. Forty seven statin-naive patients clinically indicated to LDL cholesterol-lowering therapy with atorvastatin were enrolled in a two-period crossover study. Microdose (100 µg) of atorvastatin was orally administered followed by therapeutic dose (10 mg) administration. Transport studies were performed with BCRP-expressing membrane vesicles. The dose-normalized plasma AUC following the therapeutic dose of atorvastatin was positively correlated with that following its microdose, but the AUC increased more than dose proportionally from microdose to therapeutic dose. The patients carrying SLCO1B1 c.521TC showed a significantly higher AUC compared with those carrying c.521TT following the microdose (175%) and therapeutic dose (139%). On the other hand, SLCO1B1 c.388G or ABCG2 c.421A variant alleles did not significantly affect the pharmacokinetics of atorvastatin. Atorvastatin showed ATP-dependent transport in BCRP-expressing membrane vesicles and it inhibited rosuvastatin transport with Ki of 6.3 ± 2.9 µM (mean ± SD). Microdosing study appears to be feasible to roughly estimate the pharmacokinetic and pharmacogenetic profiles of atorvastatin following the oral therapeutic dose in hypercholesterolemic patients.

Effect of coadministration of single and multiple doses of rifampicin on the pharmacokinetics of fexofenadine enantiomers in healthy subjects.

The effect of rifampicin on the pharmacokinetics of fexofenadine enantiomers was examined in healthy subjects who received fexofenadine alone or with single or multiple doses of rifampicin (600 mg). A single coadministered dose of rifampicin significantly decreased the oral clearance (CL(tot)/F) and renal clearance (CL(r)) of S- and R-fexofenadine by 76 and 62%, and 73 and 62%, respectively. Even after multiple doses, rifampicin significantly decreased these parameters, although the effect on the CL(tot)/F was slightly blunted. Multiple doses of rifampicin abolished the difference in the CL(tot)/F of fexofenadine enantiomers, whereas the stereoselectivity in the CL(r) persisted. Rifampicin inhibited the uptake of fexofenadine enantiomers by human hepatocytes via organic anion transporter (OAT) OATP1B3 and its basal-to-apical transport in Caco-2 cells, but not OAT3-mediated or multidrug and toxic compound extrusion 1 (MATE1)-mediated transport. The plasma-unbound fraction of S-fexofenadine was 1.8 times higher than that of R-fexofenadine. The rifampicin-sensitive uptake by hepatocytes was 1.6 times higher for R-fexofenadine, whereas the transport activities by OATP1B3, OAT3, MATE1, or P-glycoprotein were identical for both enantiomers. S-fexofenadine is a more potent human histamine H1 receptor antagonist than R-fexofenadine. In conclusion, rifampicin has multiple interaction sites with fexofenadine, all of which contribute to increasing the area under the curve of fexofenadine when they are given simultaneously, to surpass the effect of the induction of P-glycoprotein elicited by multiple doses.

Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP.

BACKGROUND AND PURPOSE An ATP-binding cassette (ABC) transporter, breast cancer resistance protein (BCRP)/ABCG2, limits oral bioavailability of sulphasalazine. Here we examined the effect of curcumin, the principal curcuminoid of turmeric, on oral bioavailability of microdoses and therapeutic doses of sulphasalazine in humans. EXPERIMENTAL APPROACH Effects of curcumin were measured on the ATP-dependent sulphasalazine uptake by hBCRP-expressing membrane vesicles and on oral bioavailability of sulphasalazine in wild-type and Bcrp(-/-) mice. Eight healthy Japanese subjects received an oral dose of sulphasalazine suspension (100 µg) or tablets (2 g) alone or after curcumin tablets (2 g). Uptake of sulphasalazine was studied in HEK293 cells transfected with the influx transporter (OATP)2B1. KEY RESULTS Curcumin was a potent hBCRP inhibitor in vitro (K(i) 0.70 ± 0.41 µM). Curcumin increased the area under the curve (AUC)(0-8) of plasma sulphasalazine eightfold in wild-type mice at 300 and 400 mg·kg(-1), but not in Bcrp(-/-) mice. Curcumin increased AUC(0-24) of plasma sulphasalazine 2.0-fold at microdoses and 3.2-fold at therapeutic doses in humans. Non-linearity of the dose-exposure relationship was observed between microdoses and therapeutic doses of sulphasalazine. Sulphasalazine was a substrate for OATP2B1 (K(m) 1.7 ± 0.3 µM). Its linear index (dose/K(m)) at the therapeutic dose was high and may saturate OATP2B1. CONCLUSIONS AND IMPLICATIONS Curcumin can be used to investigate effects of BCRP on oral bioavailability of drugs in humans. Besides the limited dissolution, OATP2B1 saturation is a possible mechanism underlying non-linearity in the dose-exposure relationship of sulphasalazine.