In vitro Inhibition of CYP3A4 Metabolism and P‐Glycoprotein‐Mediated Transport by Trade Herbal Products

Abstract

Extracts of six commonly used commercially available herbal products, St. John's wort, common valerian, common sage, Ginkgo biloba , Echinacea purpurea and horse chestnut were investigated for their in vitro inhibitory potential of CYP3A4 mediated metabolism and P-glycoprotein efflux transport activity. C-DNA baculovirus expressed CYP3A4 and Caco-2 cells were used. Ketoconazole and verapamil were applied as positive control inhibitors, respectively. A validated high-performance liquid chromatography methodology was used to quantify the formation of 6-OH-testosterone and scintillation counting was used to quantify the transport of 3 H-digoxin. All the investigated herbs inhibited CYP3A4 activity. St. John's wort was the strongest inhibiting herb with an IC 50 value of 15.4 μ g/ml, followed by common sage, Ginkgo biloba , common valerian, horse chestnut and Echinacea purpurea . All herbs also inhibited P-glycoprotein activity. Ginkgo biloba was the strongest inhibiting herb, inhibiting the net digoxin flux with an IC 50 value of 23.6 μ g/ml, followed by St. John's wort, horse chestnut, common sage, common valerian and Echinacea purpurea . No correlation was found between the herbs inhibitory potentials towards CYP3A4 and P-glycoprotein activities. Ginkgo biloba , horse chestnut and common sage, besides St. John's wort, are suggested candidates for in vivo intestinal herb-drug pharmacokinetic interactions.

Negligible Effect of Ginkgo Biloba Extract on the Pharmacokinetics of Cilostazol

“…Pharmacokinetic changes of cilostazol may be possible with the co-administration of the CYP inhibitor because it is metabolized mainly via CYP. There are some reports that G. biloba extract inhibited in vitro CYP 3A mediated metabolism (Zou et al, 2002;Hellum and Nilsen, 2008). The results from the present study (Table I) indicated that G. biloba extract mildly inhibits CYP2C8, CYP2C9, and CYP2C19 activities with IC50 of 30.8, 60.5, and 25.2 μg/ml, respectively, in human liver microsomes.…”

Valerian: No evidence for Clinically Relevant interactions

“…During the past decade, several potential mechanisms of interactions of valerian preparations, involving CYP enzymes, P-glycoprotein, and UGTs, have been studied in vitro [36,[38][39][40][41][42]46]. Some of these studies pointed to a possible drug interaction potential by valerian extracts.…”

“…In a follow-up study, the same preparation was used, and an IC 50 for CYP 3A4 inhibition at a concentration of 0.756 mg/mL was observed [40]. Slight but significant effects on bidirectional digoxin transport (involving P-gp) were found only with 1.875 mg/mL.…”

Herbal drugs and drug interactions

“…In an in vitro study in Caco-2 cells, it was demonstrated that the inhibitory effect of various Echinaceae extracts on CYP3A4 and P-gps showed large variability depending on the total alkamide content of the extract (101). Gorski et al (2004) studied the effect of Echinaceae on various CYP enzymes in healthy human volunteers using different probe drugs, namely caffein (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP 2D6) and midazolam (CYP3A4), and observed that it significantly reduces the clearence of only caffein (CYP1A2) and tolbutamide (CYP2C9).…”