Species difference in the inhibitory potentials of non-steroidal anti-inflammatory drugs on the hepatic sulfation and glucuronidation of bioactive flavonoids: differential observations among common inhibition parameters

Abstract

1. This study elucidated the species differences between rats and humans in the inhibitory potential of drugs against sulfation and glucuronidation, and whether such differences depend on the inhibition parameter adopted. 2. With 14 non-steroidal anti-inflammatory drugs (NSAIDs) as model inhibitors and three flavanoids baicalein, wogonin and oroxylin A as model substrates, three common inhibition parameters percentage of control, IC50 and Ki were determined in rat liver cytosols (RLCs), human liver cytosols (HLCs), rat liver microsomes (RLMs) and human liver microsomes (HLMs). The closeness of the inhibition parameters from rat liver preparations to that from human liver preparations was analyzed by geometric mean fold error (GMFE) and statistical comparisons. 3. The percentage of control in RLC/RLM was not significantly different from that in HLC/HLM, with a GMFE of 0.85 (RLC-HLC) and 1.03 (RLM-HLM); whereas the IC50 and Ki in RLC/RLM were significantly different from that in HLC/HLM. The trend of difference was consistent between IC50 and Ki, where these parameters in RLC and RLM underestimated (GMFE <0.5) and overestimated (GMFE >2) that in HLC and HLM, respectively. 4. In conclusion, the inhibitory potentials of NSAIDs against sulfation and glucuronidation in rats and humans were different and depended on the adopted inhibition parameters.

In vitro–in vivo extrapolations to evaluate the effect of concomitant drugs on tacrolimus (FK506) exposure

“…A GMFE of 1 represents perfect predictability, while GMFE values between 0.5 and 2 indicate that most of the predicted AUC p.o. fall within the 2‐fold range of the observed values .…”

“…The bias (deviation from unity) of the different prediction approaches was assessed by determining the calculated geometric mean fold error (GMFE) using the following equation : …”

Herb–drug interactions between Scutellariae Radix and mefenamic acid: Simultaneous investigation of pharmacokinetics, anti-inflammatory effect and gastric damage in rats

“…From our in vitro metabolism inhibition study using rat liver microsomes, SR extract dose-dependently inhibited the hydroxylation and glucuronidation of MEF, with IC 50 values of 60 mg/ml and 100 mg/ml, respectively (data not shown). Meanwhile, MEF competitively inhibited the glucuronidation of baicalein, wogonin, and oroxylin in rat liver microsomes with K i values of 71-743 mM (Fong and Zuo, 2014). These mechanistic studies suggested MEF and SR components might interact via metabolism inhibitions.…”

“…These similarities may increase the opportunity of co-administration by patients and, at the same time, the potential of pharmacokinetic and/or pharmacodynamic interactions. From our previous in vitro screening results among 14 NSAIDs, mefenamic acid (MEF) was the most potent inhibitor on the hepatic glucuronidation and sulfation of three major components of SR, the flavonoids baicalein, wogonin, and oroxylin A, with inhibition constants K i ranging from 5 to 195 μM (Fong and Zuo, 2014). Therefore, MEF was selected in the current study for further in vivo evaluations of its potential interaction with SR extract.…”

Pharmacokinetics of B-Ring Unsubstituted Flavones

“…As a consequence of these regioselectivities in glucuronidation of flavonoids, UGT1A8 and UGT1A9 seem to be the dominant isoforms involved in the glucuronidation of wogonin and oroxylin A, whereas UGT1A1 and UGT1A9 are involved in the glucuronidation of baicalein [163].…”