Repeated administration of berberine inhibits cytochromes P450 in humans

Abstract

Purpose Berberine is a plant alkaloid that is widely used to treat gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia. Many studies have reported interactions between berberine-containing products and cytochromes P450 (CYPs), but little is known about whether berberine alters CYP activities in humans, especially after repeated doses. Methods A two-phase randomized-crossover clinical study in healthy male subjects was performed. After 2 weeks of berberine (300 mg, t.i.d., p.o.) administration, midazolam, omeprazole, dextromethorphan, losartan, and caffeine were used to evaluate enzyme activities of CYP3A4, 2C19, 2D6, 2C9, and CYP1A2, respectively. Results A decrease in CYP2D6 activity was observed as the 0–8 h urinary dextromethorphan/dextrorphan increased ninefold (P<0.01). In addition, losartan/E-3174 ratio doubled (P<0.01) after BBR administration, indicating a decrease in CYP2C9 activity. CYP3A4 activity was also inhibited, as the Cmax, AUC0–∞, and AUC0–12 of midazolam were increased 38% (P<0.05), 40% (P<0.01), and 37% (P<0.05) after BBR treatment, respectively. Compared with the placebo period, the Tmax and T1/2 of midazolam during BBR administration were prolonged from 3.03±0.27 to 3.66±0.37 h and 0.66±0.08 to 0.99±0.09 h, respectively; the oral clearance of midazolam was decreased 27% (P< 0.05); and the phenotypic indices of 1 h midazolam/1′-hydroxymidazolam increased 59% (P<0.01). There were no statistically significant differences in the pharmacokinetic parameters of the other probe drugs between placebo and the BBR-treated group. Conclusions Repeated administration of berberine (300 mg, t.i.d., p.o.) decreased CYP2D6, 2C9, and CYP3A4 activities. Drug-drug interactions should be considered when berberine is administered.

Time-Dependent Inhibition of CYP2C19 by Isoquinoline Alkaloids: In Vitro and In Silico Analysis

“…Based on the present data, two TCM compounds, the noninhibitor berberine (43, IC 50 150 mM) and the weak CYP2C19 inhibitor sinomenine (47, IC 50 55 mM), are unlikely to affect the metabolism of drugs that are substrates of CYP2C19. Berberine (43) has been extensively studied and is a widely used constituent in herbal products (Vuddanda et al, 2010;Guo et al, 2012). The observed low CYP2C19 inhibitory potency (IC 50 150 mM) is consistent with previous in vitro (Han et al, 2011) and in vivo studies in humans (Guo et al, 2012).…”

“…Berberine (43) has been extensively studied and is a widely used constituent in herbal products (Vuddanda et al, 2010;Guo et al, 2012). The observed low CYP2C19 inhibitory potency (IC 50 150 mM) is consistent with previous in vitro (Han et al, 2011) and in vivo studies in humans (Guo et al, 2012). Sinomenine (47), extracted from the Chinese medical plant Sinomenium acutum, is used for the treatment of a variety of disorders such as rheumatism and cardiac arrhythmia.…”

Chelidonium majus L. (Greater celandine) – A Review on its Phytochemical and Therapeutic Perspectives

“…Inhibited the activity of CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP2C9, CYP3A4 CYP3A11 and CYP2D22 enzymes [133][134][135] .…”

Evaluation by microarray of the potential safety of Sarracenia purpurea L. (Sarraceniaceae) a traditional medicine used by the Cree of Eeyou Istchee

“…This was somewhat surprising as many plants have evolved secondary metabolites in order to be resistant against microbes and insects (40) and often possess compounds that inhibit CYP450 in order to potentiate their defences. Although mostly described on a protein level (41)(42)(43)(44), these changes may also occur on a transcript level (37,(45)(46)(47)(48). Furthermore, other reports have demonstrated changes to genes important for xenobiotic disposition such as ABC transporters and Phase II metabolizing enzymes in response to plant extracts, including but not limited to GSTs and QRs (48)(49)(50) all present on this array but not significantly altered.…”