Lopinavir/Ritonavir Induces the Hepatic Activity of Cytochrome P450 Enzymes CYP2C9, CYP2C19, and CYP1A2 But Inhibits the Hepatic and Intestinal Activity of CYP3A as Measured by a Phenotyping Drug Cocktail in Healthy Volunteers

  title={Lopinavir/Ritonavir Induces the Hepatic Activity of Cytochrome P450 Enzymes CYP2C9, CYP2C19, and CYP1A2 But Inhibits the Hepatic and Intestinal Activity of CYP3A as Measured by a Phenotyping Drug Cocktail in Healthy Volunteers},
  author={Rosa F. Yeh and Vincent Gaver and Kristine B. Patterson and Naser L. Rezk and Faustina Baxter-Meheux and Michael J. Blake and Joseph J. Eron and Cheri E. Klein and John C Rublein and Angela D. M. Kashuba},
  journal={JAIDS Journal of Acquired Immune Deficiency Syndromes},
  • R. Yeh, V. Gaver, A. Kashuba
  • Published 1 April 2006
  • Medicine, Biology
  • JAIDS Journal of Acquired Immune Deficiency Syndromes
Objective: The effect of lopinavir/ritonavir (LPV/r) administration on cytochrome P450 (CYP) enzyme activity was quantified using a phenotyping biomarker cocktail. Changes in CYP2C9, CYP2C19, CYP3A, CYP1A2, N-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) activities were evaluated using warfarin (WARF) + vitamin K, omeprazole (OMP), intravenous (IV) and oral (PO) midazolam (MDZ), and caffeine (CAF). Design: Open-label, multiple-dose, pharmacokinetic study in healthy volunteers. Methods… 
A Phenotype–Genotype Approach to Predicting CYP450 and P‐Glycoprotein Drug Interactions With the Mixed Inhibitor/Inducer Tipranavir/Ritonavir
Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r.
A randomised study of the effect of danoprevir/ritonavir or ritonavir on substrates of cytochrome P450 (CYP) 3A and 2C9 in chronic hepatitis C patients using a drug cocktail
Danoprevir/r and placebo/r significantly increased midazolam area under the time–concentration curve (AUC0–∞) and reduced the midazlam metabolic ratio while S-warfarin AUC0-∞ was modestly decreased.
Effect of an Antiretroviral Regimen Containing Ritonavir Boosted Lopinavir on Intestinal and Hepatic CYP3A, CYP2D6 and P‐glycoprotein in HIV‐infected Patients
CYP3A, CYP2D6, and P‐glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir, and the covariates investigated are not useful for a priori dose selection.
Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir
The results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition, despite significant inhibition of hepatic and intestinal CYP 3A activity.
Eltrombopag, an oral thrombopoietin receptor agonist, has no impact on the pharmacokinetic profile of probe drugs for cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C9 and CYP2C19 in healthy men: a cocktail analysis
Once-daily administration of eltrombopag 75 mg for 7 days did not alter CYP3A4, CYP1A2, CYB2C9 or CYP2C19 activity in healthy volunteers.
The Role of Cytochrome P450 3A Inducers and Inhibitors in the Metabolism and the Effects of Oxycodone
Clinicians should avoid concomitant administration of CYP3A inducers or inhibitors and oral oxycodone if this is not possible, and be prepared to interactions leading to impaired analgesia or increased adverse effects after CYP2D6 inducers and oral Oxycodone.
Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study
The results demonstrate that exposures of probes of CYP3A4, CYP2D6, or CYP 2C19 activity are potentially altered by administration of sorafenib at 400 mg twice daily, however, these differences are sufficiently small that a clinically significant inhibition or induction of these important drug metabolizing P450 isoenzymes is unlikely.
Pharmacodynamics of Carbamazepine‐mediated Induction of CYP3A4, CYP1A2, and Pgp as Assessed by Probe Substrates Midazolam, Caffeine, and Digoxin
The possibility of modeling the pharmacodynamics of enzyme induction using a turnover model was illustrated, and the time course of the process was estimated with good precision.
CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4β-hydroxycholesterol levels
Changes in plasma 4β-hydroxycholesterol following the initiation of efavirenz- or atazanavir/ritonavir-based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens.
Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects
The results suggest that GBE induces CYP3A metabolism, as assessed by a decrease in midazolam concentrations, which appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted proteins may be affected.


Coadministration of Lopinavir/Ritonavir and Phenytoin Results in Two-Way Drug Interaction Through Cytochrome P-450 Induction
Concomitant LPV/RTV and PHT use results in a 2-way drug interaction, and Phenytoin appears to increase LPV clearance via CYP3A4 induction, which is not offset by the presence of low-dose RTV.
Different contribution of CYP2C19 in the in vitro metabolism of three proton pump inhibitors.
A comparative in vitro study was conducted using the human liver microsomes and newly developed anti-human CYP antibodies, and the relative contribution of CYP2C19 on total metabolism of 3 PPIs elucidated herein coincided with the CYP1C19 genotype-dependent pharmacokinetics.
Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole.
The results show that G biloba can induce omeprazole hydroxylation in a CYP2C19 genotype-dependent manner and concurrently reduce the renal clearance of 5-hydroxyomeprazole.
Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations.
YP1A2 activity is the major determinant of caffeine clearance and the paraxanthine/caffeine ratios in vivo, of which the saliva ratio 6 h postdose appears as the most advantageous parameter.
Apparent mechanism‐based inhibition of human CYP3A in‐vitro by lopinavir
Although lopinavir is less potent than ritonavir as an inhibitor of CYP3A, lop Scandinavir is nonetheless likely to contribute to net CYP1A2, 2B6, 2C9, 2D19 and 2D6 inhibition in‐vivo during treatment with the lopinvir‐ritonavir combination.
Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug interaction.
The combination of ABT-378 and ritonavir was much weaker in inhibiting CYP-mediated biotransformations than ritonivir alone, and the inhibitory effect appears to be primarily due to the ritonvir component of the combination.
Mechanism-Based Inactivation of CYP3A by HIV Protease Inhibitors
All the PIs exhibited mechanism-based inactivation, and predictions of the extent and time course of drug interactions with PIs could be underestimated if based solely on reversible inhibition.
Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir
Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinvir soft-gel capsules and lipinavir/ritonavir, and this boosted double PI combination could be an effective option for patients with limited RTI options.