Effect of Simultaneous Induction and Inhibition of CYP3A by St John's Wort and Ritonavir on CYP3A Activity

• Published in: Clinical pharmacology and therapeutics Vol. 87; no. 2; pp. 191 - 196
• Main Authors: Hafner, V, Jäger, M, Matthée, A‐K, Ding, R, Burhenne, J, Haefeli, W E, Mikus, G
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-02-2010
• Subjects: Administration, Oral; Adult; Area Under Curve; Biological and medical sciences; Cytochrome P-450 CYP3A - drug effects; Cytochrome P-450 CYP3A - metabolism; Drug Interactions; Enzyme Induction - drug effects; Enzyme Inhibitors - pharmacology; Female; HIV Protease Inhibitors - pharmacology; Humans; Hypericum - chemistry; Infusions, Intravenous; Male; Medical sciences; Midazolam - administration & dosage; Midazolam - pharmacokinetics; Pharmacology. Drug treatments; Plant Extracts - pharmacology; Ritonavir - pharmacology; Substance Withdrawal Syndrome; Young Adult; Human; Hypericum perforatum; Antiretroviral agent; Enzyme; Pharmacognosy; Induction; Isozyme; Psychotropic; Ritonavir; Guttiferae; Cytochrome P450; Enzyme inhibitor; Extract; Biological activity; Medicinal plant; Peptidases; Dicotyledones; Angiospermae; Hydrolases; Antidepressant agent; Antiviral; Spermatophyta; Inhibition; Protease inhibitor
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/clpt.2009.206

We aimed to assess the effect of coadministration and withdrawal of a potent cytochrome P450 3A (CYP3A) inhibitor (ritonavir) and a potent CYP3A inducer (St John's wort) on CYP3A enzyme activity in an open, fixed‐sequence study design. We investigated the pharmacokinetics of midazolam: (i) at baseline, (ii) after a single dose of either St John's wort or ritonavir (each n = 6), (iii) after 14 days of coadministration of ritonavir (300 mg b.i.d.) and St John's wort (300 mg t.i.d.), and (iv) at 2 days after cessation of both St John's wort and ritonavir. Combined administration of inducer and inhibitor resulted in a predominance of enzyme inhibition: coadministration of St John's wort and ritonavir with intravenous administration of midazolam resulted in an increase in the area under the plasma concentration–time curve (AUC)0–8 h of midazolam to 180% of baseline value, whereas with orally administered midazolam, the AUC0–6 h increased to 412% of baseline value (P < 0.05 for each). After cessation of the coadministered drugs, the AUC0–6 h of orally administered midazolam decreased to 6% of the level observed during combined administration, and the AUC0–8 h of intravenously administered midazolam decreased to 33% of the values observed during combined administration (P < 0.001 for each). Induction may be unmasked after the withdrawal of a combination of a potent CYP3A inhibitor and a potent CYP3A inducer, leading to substantial drops in drug exposure of CYP3A substrates. This may require substantial dose adjustments, particularly of orally administered drugs.
Clinical Pharmacology & Therapeutics (2010) 87 2, 191–196. doi:10.1038/clpt.2009.206