Herb-drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7.

Herb-drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (Ki) were determined for the compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (Ki) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb-drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7.

Glucuronidation of aurantio-obtusin: identification of human UDP-glucuronosyltransferases and species differences.

1. The aurantio-obtusin's glucuronide was detected when aurantio-obtusin was incubated with human liver microsomes (HLMs). Recombinant UGT isoforms screening experiment showed that UGT1A8 was the major isoform contributed to the glucuronidation. 2. The metabolic profiles for aurantio-obtusin in liver microsomes from different species were similar, however, the intrinsic clearance values (Vmax/Km) among the species were: Monkey > Human > Rat > Rabbit > Dog > Pig > Mouse > Guinea pig.

Onset of cooperation between layered networks.

Functionalities of a variety of complex systems involve cooperations among multiple components; for example, a transportation system provides convenient transfers among airlines, railways, roads, and shipping lines. A layered model with interacting networks can facilitate the description and analysis of such systems. In this paper we propose a model of traffic dynamics and reveal a transition at the onset of cooperation between layered networks. The cooperation strength, treated as an order parameter, changes from zero to positive at the transition point. Numerical results on artificial networks as well as two real networks, Chinese and European railway-airline transportation networks, agree well with our analysis.

Reversible inhibition of four important human liver cytochrome P450 enzymes by diethylstilbestrol.

Diethylstilbestrol (DES), a synthetic estrogen clinically used to treat threatened abortion between the 1940s and the 1970s, has been restricted to treat certain cases of prostatic and breast cancer due to its adverse drug responses such as teratogenicity and carcinogenicity. Some reports have demonstrated that the addition of DES to docetaxel could modify tubulin composition and improve response of prostate cancer to chemotherapy. Given that DES might be co-administered with other drugs such as docetaxel, the present study focused on CYP-based drug-drug interaction (DDI). In vitro inhibitory effects of DES on CYP isoforms were investigated, and the results showed that DES could competitively inhibit CYP3A4, CYP2C8, CYP2C9 and CYP2E1. The inhibition constants (Ki) were calculated to be 4.4 microM, 3.0 microM, 5.0 microM and 8.0 microM for CYP3A4, CYP2C9, CYP2E1 and CYP2C8, respectively. Based on peak serum DES level after drip influsion of 500 mg of fosfestrol (DES diphosphate) in patients, [I]/Ki was calculated to be 4.3, 6.2, 3.7 and 2.3 for CYP3A4, CYP2C9, CYP2E1 and CYP2C8, which suggested that DES was likely to induce in vivo DDI through inhibition of these four major CYP isoforms. These results collectively demonstrate that adverse drug responses might exist when DES is co-administered with other drugs.

Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib.

AIM: To ascertain the effects of erlotinib on CYP3A, to investigate the amplitude and kinetics of erlotinib-mediated inhibition of seven major CYP isoforms in human liver microsomes (HLMs) for evaluating the magnitude of erlotinib in drug-drug interaction in vivo. METHODS: The activities of 7 major CYP isoforms (CYP1A2, CYP2A6, CYP3A, CYP2C9, CYP2D6, CYP2C8, and CYP2E1) were assessed in HLMs using HPLC or UFLC analysis. A two-step incubation method was used to examine the time-dependent inhibition of erlotinib on CYP3A. RESULTS: The activity of CYP2C8 was inhibited with an IC(50) value of 6.17±2.0 µmol/L. Erlotinib stimulated the midazolam 1'-hydroxy reaction, but inhibited the formation of 6ß-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substrate-dependent: the IC(50) values for inhibiting testosterone 6ß-hydroxylation and nifedipine metabolism were 31.3±8.0 and 20.5±5.3 µmol/L, respectively. Erlotinib also exhibited the time-dependent inhibition on CYP3A, regardless of the probe substrate used: the value of K(I) and k(inact) were 6.3 µmol/L and 0.035 min(-1) for midazolam; 9.0 µmol/L and 0.045 min(-1) for testosterone; and 10.1 µmol/L and 0.058 min(-1) for nifedipine. CONCLUSION: The inhibition of CYP3A by erlotinib was substrate-dependent, while its time-dependent inhibition on CYP3A was substrate-independent. The time-dependent inhibition of CYP3A may be a possible cause of drug-drug interaction, suggesting that attention should be paid to the evaluation of erlotinib's safety, especially in the context of combination therapy.