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

Yeh, Rosa F.; Gaver, Vincent E.; Patterson, Kristine B.; Rezk, Naser L.; Baxter-Meheux, Faustina; Blake, Michael; Eron, Joseph J.; Klein, Colin; Rublein, John; Kashuba, Angela D. M.

doi:10.1097/01.qai.0000219774.20174.64

Cited by 169 publications

(140 citation statements)

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“…It is a substrate and inhibitor of CYP3A4 and to a lesser extent CYP2D6, and an inducer of CYP1A2, 2B6, 2C9 and 2C19 [23,24] which makes it prone to cytochrome P450-mediated interactions.…”

Section: Discussionmentioning

confidence: 99%

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Nieminen

Hagelberg

Saari

et al. 2010

Eur J Clin Pharmacol

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To cite this version:Methods: A randomized crossover study design with 3 phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioural effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis.Results: Ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-(range 1.9-to 4.3-fold; P<0.001) and 2.6-fold (range 1.9-to 3.3-fold; P<0.001). The mean (± SD) elimination half-life prolonged after ritonavir and lopinavir/ritonavir from 3.6 ± 0.6 to 5.6 ± 0.9 h (P<0.001) and 5.7 ± 0.9 h (P<0.001), respectively. Both ritonavir (P<0.001) and lopinavir/ritonavir (P<0.05) increased the self-reported drug effect of oxycodone. Conclusions:Ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse-effects.

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“…It is a substrate and inhibitor of CYP3A4 and to a lesser extent CYP2D6, and an inducer of CYP1A2, 2B6, 2C9 and 2C19 [23,24] which makes it prone to cytochrome P450-mediated interactions.…”

Section: Discussionmentioning

confidence: 99%

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Nieminen

Hagelberg

Saari

et al. 2010

Eur J Clin Pharmacol

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“…Effects of shorter-duration (2 days) ritonavir-lopinavir on CYP3A were even greater, causing 91% inhibition of oral alfentanil clearance. Previously, combined hepatic and intestinal CYP3A and hepatic CYP3A activities were inhibited by ritonavir-lopinavir by 92% and 77%, respectively (Yeh et al, 2006), and 82% and 76%, respectively (Wyen et al, 2008), as assessed by apparent oral and i.v. midazolam clearances.…”

Section: Controlmentioning

confidence: 99%

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Kharasch

Stubbert

2013

Drug Metab Dispos

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Plasma concentrations of orally administered methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavirlopinavir on intravenous and oral methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. Plasma and urine concentrations of methadone and metabolite enantiomers, and other analytes, were determined by mass spectrometry. Acute and chronic ritonavir-lopinavir reduced plasma methadone enantiomer concentrations in half, with an average 2.6-and 1.5-fold induction of systemic and apparent oral methadone clearances. Induction was attributable to stereoselectively increased hepatic methadone N-demethylation, hepatic extraction, and hepatic clearance, and there was a strong correlation between methadone N-demethylation and clearance. Methadone renal clearance was unchanged. Alfentanil's systemic clearance and hepatic extraction, apparent oral clearance, and intestinal extraction were reduced to 25%, 16%, and 35% of control, indicating strong inhibition of hepatic and intestinal CYP3A activities. Ritonavir-lopinavir (acute > chronic) increased fexofenadine exposure, suggesting intestinal P-glycoprotein inhibition. No correlation was found between methadone clearance and CYP3A activity. Acute and steady-state ritonavir-lopinavir stereoselectively induced methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir-lopinavir inhibited intestinal transporters activity but had no effect on methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition.

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“…12 The increased enzymatic activity of CYP2C9 and CYP1A2 induced by lopinavir/ritonavir may reduce S-and Rwarfarin levels, thus accounting for the reduction in INR and the increased warfarin dose required to maintain the patient's INR in the therapeutic range.…”

mentioning

confidence: 99%

Interaction between lopinavir/ritonavir and warfarin

Hughes¹,

Freitas²,

Miedzinski³

2007

Canadian Medical Association Journal

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A 42-year-old man was admitted to hospital with chills and progressive shortness of breath on exertion. He had received an aortic valve replacement 12 years before presentation and had been taking warfarin since that time. A diagnosis of pneumonia caused by Pneumocystis jiroveci was made and was confirmed by Giemsa staining of bronchoscopy specimens. Serologic testing revealed a positive HIV status, with a baseline CD4 cell count of 150 × 10 6 /L. The patient's pneumonia was treated with high-dose co-trimoxazole therapy and a tapering course of steroids. In addition, daily fluconazole therapy was initiated for the treatment of candidiasis, and citalopram for the treatment of depression. In the year before he was admitted to hospital, the patient had been taking warfarin (5.5 mg/d) to maintain his international normalized ratio (INR) between 2 and 3. Five days after discharge from hospital, his INR was 4.4. Warfarin was held for 1 dose and was then resumed at an alternating dose of 3 mg/d and 3.5 mg/d. Three days and 2 weeks later the INR was 3.8 and 2.1 respectively. Two weeks after discharge, co-trimoxazole therapy was decreased to a prophylactic dose (1 doublestrength dose daily). One month after discharge, the patient was prescribed antiretroviral therapy (zidovudine, lamivudine and lopinavir/ritonavir). At that time, in addition to warfarin, he was taking co-trimoxazole, fluconazole daily, citalopram, clonazepam, zopiclone and pantoprazole. He was instructed to reduce fluconazole therapy from daily to weekly, and the co-trimoxazole therapy was decreased from double to single strength.Following initiation of the lopinavir/ritonavir therapy, the patient's INR decreased substantially, with repeated values between 1.1 and 1.3. At a follow-up visit 1 month after initiation of the lopinavir/ritonavir, the patient reported that he had continued taking fluconazole daily despite instructions to decrease it to once weekly. The fluconazole therapy was discontinued at that time, and repeat testing over the next few weeks revealed INR values between 1.0 and 1.3. We ruled out patient nonadherence as well as changes in diet as possible explanations for the continued low INRs. The warfarin dose was titrated by his family physician over several months to a dose of 11 mg/d. His INR remained subtherapeutic during this period. Six months after fluconazole was discontinued his INR was 2.6. The patient was referred to the anticoagulation management service, and 1 month later his INR had stabilized between 2 and 3 (at a warfarin dose of about 13 mg/d). He continued to take antiretroviral medications, as well as the other prescribed medications, during this period. Seven months after initation of the antiretroviral therapy, the patient's CD4 cell count had risen to 330 × 10 6 /L, and his HIV viral load was < 50 copies/mL. CommentsLopinavir/ritonavir (a co-formulation of lopinavir and ritonavir) is recommended as a preferred protease inhibitor for the treatment of HIV in patients who have not previously received antiretroviral thera...

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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

Cited by 169 publications

References 59 publications

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Interaction between lopinavir/ritonavir and warfarin

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