Effect of simultaneous induction and inhibition of CYP3A by St John's Wort and ritonavir on CYP3A activity.
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 AUC(0-6 h) increased to 412% of baseline value (P < 0.05 for each). After cessation of the coadministered drugs, the AUC(0-6 h) of orally administered midazolam decreased to 6% of the level observed during combined administration, and the AUC(0-8 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.
Hafner
V
V
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
Jäger
M
M
Matthée
A-K
AK
Ding
R
R
Burhenne
J
J
Haefeli
W E
WE
Mikus
G
G
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010936:Plant Extracts / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome; D055815:Young Adult
D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D010936:Plant Extracts; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D008874:Midazolam