Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter lopinavir-ritonavir exposure in healthy subjects.
OBJECTIVE
. To determine the influence of Echinacea purpurea on the pharmacokinetics of lopinavir-ritonavir and on cytochrome P450 (CYP) 3A and P-glycoprotein activity by using the probe substrates midazolam and fexofenadine, respectively.


METHODS
Open-label, single-sequence pharmacokinetic study.


METHODS
Outpatient clinic in a federal government research center.


METHODS
Thirteen healthy volunteers (eight men, five women).


METHODS
Subjects received lopinavir 400 mg-ritonavir 100 mg twice/day with meals for 29.5 days. On day 16, subjects received E. purpurea 500 mg 3 times/day for 28 days: 14 days in combination with lopinavir-ritonavir and 14 days of E. purpurea alone. In order to assess CYP3A and P-glycoprotein activity, subjects received single oral doses of midazolam 8 mg and fexofenadine 120 mg, respectively, before and after the 28 days of E. purpurea.


RESULTS
On days 15 and 30 of lopinavir-ritonavir administration (before and after E. purpurea administration, respectively), serial blood samples were collected over 12 hours to determine lopinavir and ritonavir concentrations and subsequent pharmacokinetic parameters by using noncompartmental methods. Neither lopinavir nor ritonavir pharmacokinetics were significantly altered by 14 days of E. purpurea coadministration. The post-echinacea: pre-echinacea geometric mean ratios (GMRs) for lopinavir area under the concentration-time curve (AUC) from 0-12 hours and for maximum concentration were 0.96 (90% confidence interval [CI] 0.83-1.10, p=0.82) and 1.00 (90% CI 0.88-1.12, p=0.72), respectively. Conversely, GMRs for midazolam AUC from time zero extrapolated to infinity and oral clearance were 0.73 (90% CI 0.61-0.85, p=0.008) and 1.37 (90% CI 1.10-1.63, p=0.02), respectively. Fexofenadine pharmacokinetics did not significantly differ before and after E. purpurea administration (p>0.05).


CONCLUSIONS
Echinacea purpurea induced CYP3A activity but did not alter lopinavir concentrations, most likely due to the presence of the potent CYP3A inhibitor, ritonavir. Echinacea purpurea is unlikely to alter the pharmacokinetics of ritonavir-boosted protease inhibitors but may cause modest decreases in plasma concentrations of other CYP3A substrates.
Penzak
Scott R
SR
Clinical Pharmacokinetics Research Laboratory, Pharmacy Department, National Institutes of Health, Bethesda, MD 20892, USA. spenzak@mail.cc.nih.gov
Robertson
Sarah M
SM
Hunt
Jennifer D
JD
Chairez
Cheryl
C
Malati
Christine Y
CY
Alfaro
Raul M
RM
Stevenson
James M
JM
Kovacs
Joseph A
JA
D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000378:metabolism; D004338:Drug Combinations; D020900:Echinacea; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D005260:Female; D041743:Herb-Drug Interactions / Q000502:physiology; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D010936:Plant Extracts / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage*; D019438:Ritonavir / Q000008:administration & dosage*; D055815:Young Adult
D004338:Drug Combinations; D010936:Plant Extracts; D011744:Pyrimidinones; D061466:Lopinavir; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir