The antidepressant effect of hypericum perforatum extract Ze 117 is associated with less possibility of drug interactions than hypericum perforatum extract LI 160.

Inmaculada Bellido, Maria-Rosario Cabello, Encarnacion Blanco, Elisa-Isabel Marquez, Maria-Victoria Bellido, Aurelio Gomez-Luque. University of Malaga, Malaga, Spain

Hypericum perforatum (HP) is the most extensively investigated medicinal herb with antidepressant effect. Differences shown by HP extracts in their antidepressant effects and the clinical consequences of HP extract-drug interactions have been related to different HP extracts composition, particularly regarding their primary ingredients hyperforin and hypericin. Experimental data and clinical trials have shown that low-hyperforin-content HP has a comparable antidepressant efficacy to synthetic antidepressants in the treatment of mild/moderate depression (1) (2). However, hyperforin is responsible for CYP3A4 induction via activation of a nuclear steroid/pregnane and xenobiotic receptor (SXR/PXR) and hypericin is a P-glycoprotein inducing compound (3), which are the main causes of HP-drug interactions. Some of the reported interactions are based on findings from in vitro studies but their clinical significance remains unclear. Two hypericum extracts with different hyperforin contents, Ze 117 (0.15-0.25% hypericin, 0.5% hyperforin) and LI 160 (0.3% hypericin, 4-6% hyperforin) were examined vs. classical antidepressants. HP antidepressant effects were quantified with and without hepatic CYP 450 enzyme modulation by cimetidine.

Experimental procedures followed the ECC Directives and were approved by local authorities. Male Wistar rats (n=6 per group, 6 months old, weight 314±25 g, Charles River-Spain) were injected (i.p. once a day) with Ze 117 (20 mg/kg, Zeller AG), LI 160 (20 mg/kg, Lichtwer Pharma AG), imipramine (IMI) (10.9 mg/kg, Novartis SL), fluoxetine (FLU) (5 mg/kg, Lilly and Dista) or saline (SAL), in presence and absence of cimetidine (CIM) (50 mg/kg, Rimsa) during 20 days. The forced swim test (4) was used for evaluation of the antidepressant-like effect. The open-field test was used for evaluation of the motor activity (5). The total CYP450 content of the liver was measured using a spectrophotometric method in liver microsomes (6). Results are expressed as mean ± s.e.m. and were compared by Student t test or ANOVA test followed by Bonferroni post-test.

The hypericum extracts antidepressant effects (reduction of immobility time) ranking order was: i) Without liver CYP450 inhibition by cimetidine: IMI 109±33s*** >Ze 117 163±21s =FLU165±29s** >LI 160 201±234s >SAL 224±17s, p<0.05; ii) With liver CYP450 inhibition by cimetidine: IMI 113±27s** >LI 160 144±13s** >FLU 171±21s* >Ze 117 188±10* >SAL 219±20s, *p<0.05). Motor activity reduction ranking order was: IMI >LI 160 >Ze 117 >SAL, p<0.05). LI 160 significantly reduced the liver CYP450 total content with respect to SAL (-43.3%, p<0.05) while Ze 117 had a lower effect (-25.9%, p<0.05).

Normal liver cytochrome P450 function was related to hypericum extract Ze 117 antidepressant effect and absence of antidepressant effect of LI 160. LI 160 biotransformation by liver cytochrome P450 clearly reduced its antidepressant effects. Hypericum extract LI 160 seems to be more likely to cause herb-drug interactions than Ze 117.

(1) Fiebich BL et al, Fitoterapia 82(3):474, 2011

(2) Singer A et al, Phytomedicine 18(8-9):739, 2011

(3) Mannel M, Drug Saf 27(11):773, 2004

(4) Castagné V et al, Curr Protoc Neurosci 55:8,10A1-8, 2011

(5) Consoni FT et al, Eur Neuropsychopharmacol 16(6):451, 2006

(6) Choi SJ et al, J Biochem Mol Biol 36(3):332, 2003