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Impact of African herbal medicines on antiretroviral metabolism

Mills, Edwarda,e; Foster, Brian Cb; Heeswijk, Rolf vanc; Phillips, Elizabethd; Wilson, Kumanand; Leonard, Blaird; Kosuge, Kazuhirod; Kanfer, Isadoref

RESEARCH LETTER

We examined the effects of two African herbal medicines recommended for HIV/AIDS patients on antiretroviral metabolism. Extracts from Hypoxis and Sutherlandia showed significant effects on cytochrome P450 3A4 metabolism and activated the pregnane X receptor approximately twofold. P-glycoprotein expression was inhibited, with Hypoxis showing 42–51% and Sutherlandia showing 19–31% of activity compared with verapamil. Initiating policies to provide herbal medicines with antiretroviral agents may put patients at risk of treatment failure, viral resistance or drug toxicity.

aDepartment of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

bUniversity of British Columbia, British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada

cDivision of Infectious Diseases, Ottawa General Hospital, Ottawa, Ontario, Canada

dDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada

eCanadian College of Naturapathic Medicine, Toronto, Ontario, Canada

fFaculty of Pharmacy, Rhodes University, Grahamstown, South Africa

Received 13 August, 2004

Revised 8 September, 2004

Accepted 27 September, 2004

Sponsorship: This study was funded by the Ontario HIV Treatment Network.

With over 40 million people worldwide infected with the HIV virus, the World Health Organization has embarked on an ambitious plan to have 3 million people taking antiretroviral therapy by 2005. The large-scale production of generic antiretroviral drugs will allow increased access for impoverished patients. In response to the crisis, the South African National Department of Health has recently accredited 27 facilities, whose mandate to provide AIDS care includes the provision of ‘interventions that delayed the progression of the disease, including nutritional and micronutrient supplementations, and providing complementary and traditional medicines’ [1,2].

Many antiretroviral medications, such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors are predominantly metabolized through the CYP3A4 oxidative metabolic pathway, and in the case of HIV protease inhibitors are also substrates for drug transporters such as P-glycoprotein. Herbal medications have been shown to affect the serum levels of antiretroviral medication through their effects on CYP3A4 metabolism and P-glycoprotein [3]. In addition, some herbal medications are also known to interact with nuclear receptors such as the pregnane X receptor (PXR), which modulates the expression of CYP3A4, and P-glycoprotein. We analysed the effect of two herbs in common medical use for HIV in Africa, Hypoxis hemerocallidea (African potato) and Sutherlandia, for their potential to cause drug interactions with common antiretroviral agent metabolizing mechanisms in vitro [2].

We used a previously described [4] microsome-based in-vitro fluorometric microtitre plate assay to assess the inhibitory capacities of several different preparations of commercially purchased Hypoxis and Sutherlandia towards CYP3A4. Capsules, tablets or teas of each herb were water extracted and methanol extracted and tested for the ability to inhibit CYP3A4 by the inhibition of conversion of dibenzylfluorescein to fluorescein with a measurement of fluorescence at 538 nm. Individual samples were tested in triplicate with appropriate controls for intrinsic fluorescence and quenching, and each assay was repeated for reproducibility. PXR was measured using a CYP3A4 luciferase reporter gene construct in HepG2 cells, as described in Goodwin et al. [5]. Human P-glycoprotein inhibition was assessed measuring the orthovanadate-sensitive release of phosphate and adenosine triphosphatase activity using human PGP (MDR-1) membranes from BD Gentest (New Jersey, USA), as recommended by the supplier. Statistical significance was evaluated using the one-way analysis of variance followed by Dunnet's test, P values of less than 0.05 were considered significant.

Aliquots of water extracts of Hypoxis from bulk ground botanical (A and B) and capsulated material (C) showed a significant inhibition of CYP3A4 activity at an initial concentration of 100 mg/ml, with an increase in inhibition seen with the methanol extract (Table 1). Sutherlandia aliquots showed even greater inhibition of CYP3A4 with both water and methanol extracts at 100 mg/ml, exhibiting almost complete inhibition with the methanol extract. In the PXR assay, exposure to both Hypoxis and Sutherlandia resulted in significant activation of PXR in a dose-dependent manner (Hypoxis P = < 0.05 and Sutherlandia P = < 0.01). Analysis of adenosine triphosphatase activity indicated that both Hypoxis and Sutherlandia show moderate activity of the P-glycoprotein enzyme, with the samples of Hypoxis showing 42–51% and Sutherlandia showing 19–31% of the activity strength of the known P-glycoprotein inhibitor verapamil.

Table 1

Table 1

Our findings have identified the potential for clinically significant drug interactions for both H. hemerocallidea and Sutherlandia showing in-vitro inhibition of CYP3A4 and P-glycoprotein expression. Further in-vitro studies demonstrated the propensity for activation of PXR, a nuclear receptor that controls the activation of both P-glycoprotein and CYP3A4. The combination of these findings suggest that the co-administration of these drugs with antiretroviral agents may result in the early inhibition of drug metabolism and transport followed by the induction of decreased drug exposure with more prolonged therapy. These results highlight the extreme caution that should be taken in introducing herbal drugs into the routine care of HIV patients in any setting including the developing world, and underscore the need for appropriately designed pharmacokinetic studies to unveil the true drug interaction potential of herbal drugs with antiretroviral agents. Failure to do this may result in bidirectional drug interactions, which may put patients at risk of treatment failure, viral resistance or drug toxicity. Given the Global Fund's recent announcement of funds to make antiretroviral therapy widely available in Africa, and the South African Ministry of Health, along with member states’ and non-governmental organizations’ endorsement of traditional African herbs such as Hypoxis and Sutherlandia as HIV/AIDS remedies [2], policy makers and the research community should make investigations into the clinical ramifications of the use of these herbs on antiretroviral therapy an urgent priority.

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References

1. ART roll-out begins today. Sunday Times, South Africa. Available at: http://www.sundaytimes.co.za/zones/sundaytimes/newsst/newsst1080795554.asp Accessed 13 August 2004.
2. South African Development Committee. Ministerial consultative meeting on nutrition and HIV/AIDS. Johannesburg, South Africa; 20 January 2002.
3. Mills E, Montori V, Perri D, Phillips E, Koren G. Natural health products–HIV drug interactions: a systematic review. Int J STD AIDS 2004; in press.
4. Foster BC, Foster MS, Vandenhoek S, Krantis A, Budzinski JW, Arnason JT, et al. An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic. J Pharm Pharm Sci 2001; 4:176–184.
5. Goodwin B, Hodgson E, Liddle C. The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 1999; 56:1329–1339.
© 2005 Lippincott Williams & Wilkins, Inc.