Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P-glycoprotein in human immunodeficiency virus (HIV)-infected patients receiving an antiretroviral therapy (ART) containing ritonavir boosted lopinavir, and to identify factors influencing ritonavir and lopinavir pharmacokinetics. We measured activities of CYP3A, CYP2D6, and P-glycoprotein in 28 patients before and during ART using a cocktail phenotyping approach. Activities, demographics, and genetic polymorphisms in CYP3A, CYP2D6, and P-glycoprotein were tested as covariates. Oral midazolam clearance (overall CYP3A activity) decreased to 0.19-fold (90% confidence interval (CI), 0.15-0.23), hepatic midazolam clearance and intestinal midazolam availability changed to 0.24-fold (0.20-0.29) and 1.12-fold (1.00-1.26), respectively. In CYP2D6 extensive metabolizers, the plasma ratio AUC(dextromethorphan)/AUC(dextrorphan) increased to 2.92-fold (2.31-3.69). Digoxin area under the curve (AUC)(0-12) (P-glycoprotein activity) increased to 1.81-fold (1.56-2.09). Covariates had no major influence on lopinavir and ritonavir pharmacokinetics. In conclusion, CYP3A, CYP2D6, and P-glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir. The covariates investigated are not useful for a priori dose selection.
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PMID:Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients. 1818 34

CYP3A5 genotype has no impact on the trough plasma concentrations of lopinavir and ritonavir in human immunodeficiency virus (HIV)-infected individuals on stable highly active antiretroviral therapy (HAART). This is ascribed to a drug interaction, such that ritonavir by inhibiting CYP3A activity, may occlude the pharmacokinetic consequences of functional polymorphisms in the CYP3A5 gene. In the clinical setting, where lopinavir and ritonavir are always combined, CYP3A5 genotype is of no consequence on the trough plasma concentrations of these drugs.
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PMID:CYP3A5 genotype has no impact on plasma trough concentrations of lopinavir and ritonavir in HIV-infected subjects. 1828 82

The plasma concentrations of orally administered anti-human immunodeficiency virus protease inhibitors are significantly reduced during human and mouse pregnancy. We have shown that in the mouse, at gestational day 19, this reduction is due to increased hepatic cytochrome P450 3a (Cyp3a) protein expression and activity. In the current study, we investigated the mechanisms by which Cyp3a activity is increased by pregnancy and the time course of change in expression of Cyp3a and P-glycoprotein (P-gp) in various tissues. We found that hepatic transcripts of Cyp3a16, Cyp3a41, and Cyp3a44 were significantly increased during pregnancy, whereas those of Cyp3a11 and Cyp3a25 were significantly decreased. This resulted in a net increase in Cyp3a protein expression and activity in the liver during pregnancy. The increase in Cyp3a41 and Cyp3a44 transcripts was positively correlated (p < 0.05) with hepatocyte nuclear factor 6 and estrogen receptor-alpha transcripts. The pregnancy-related factors that transcriptionally activated mouse Cyp3a isoforms also activated the human CYP3A4 promoter in pregnant CYP3A4-promoter-luciferase transgenic (CYP3A4-tg) mice. In contrast, intestinal Cyp3a protein expression was not significantly affected by pregnancy. No change in P-gp protein expression was observed in the liver or kidney during pregnancy, although a significant decrease was observed in the placenta. Because hepatic CYP3A activity also seems to be induced during human pregnancy, the mouse (including CYP3A4-tg mouse) seems to be an excellent animal model to determine the molecular mechanisms for such an induction.
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PMID:Effect of pregnancy on cytochrome P450 3a and P-glycoprotein expression and activity in the mouse: mechanisms, tissue specificity, and time course. 1850 67

Cytochrome P450 3A4 (CYP3A4), the most abundant human cytochrome P450 in liver, participates in the metabolism of approximately 50% of clinically used drugs. The pregnane X receptor (PXR), a member of the nuclear receptor superfamily, is the major activator of CYP3A4 transcription. However, because of species differences in response to PXR ligands, it is problematic to use rodents to assess CYP3A4 regulation and function. The generation of double transgenic mice expressing human PXR and CYP3A4 (TgCYP3A4/hPXR) would provide a solution to this problem. In the current study, a TgCYP3A4/hPXR mouse model was generated by bacterial artificial chromosome transgenesis in Pxr-null mice. In TgCYP3A4/hPXR mice, CYP3A4 was strongly induced by rifampicin, a human-specific PXR ligand, but not by pregnenolone 16alpha-carbonitrile, a rodent-specific PXR ligand. Consistent with CYP3A expression, hepatic CYP3A activity increased approximately 5-fold in TgCYP3A4/hPXR mice pretreated with rifampicin. Most antihuman immunodeficiency virus protease inhibitors are CYP3A substrates and their interactions with rifamycins are a source of major concern in patients coinfected with human immunodeficiency virus and Mycobacterium tuberculosis. By using TgCYP3A4/hPXR mice, human PXR-CYP3A4-mediated rifampicin-protease inhibitor interactions were recapitulated, as the metabolic stability of amprenavir, nelfinavir, and saquinavir decreased 52, 53, and 99%, respectively, in the liver microsomes of TgCYP3A4/hPXR mice pretreated with rifampicin. In vivo, rifampicin pretreatment resulted in an approximately 80% decrease in the area under the serum amprenavir concentration-time curve in TgCYP3A4/hPXR mice. These results suggest that the TgCYP3A4/hPXR mouse model could serve as a useful tool for studies on CYP3A4 transcription and function in vivo.
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PMID:A double transgenic mouse model expressing human pregnane X receptor and cytochrome P450 3A4. 1879 5

Saquinavir, a potent human immunodeficiency virus protease inhibitor, is extensively metabolized by CYP3A4. Saquinavir is coadministered with ritonavir, a strong CYP3A4 inhibitor, to boost its exposure. Ketoconazole is a potent CYP3A inhibitor. The objectives of this study were to investigate the effect of ketoconazole on the pharmacokinetics of saquinavir/ritonavir and vice versa using the approved dosage regimens of saquinavir/ritonavir at 1,000/100 mg twice daily and ketoconazole at 200 mg once daily. This was an open-label, randomized two-arm, one-sequence, two-period crossover study in healthy subjects. In study arm 1, 20 subjects received saquinavir/ritonavir treatment alone for 14 days, followed in combination with ketoconazole treatment for 14 days. In arm 2, 12 subjects received ketoconazole treatment for 6 days, followed in combination with saquinavir/ritonavir treatment for 14 days. The pharmacokinetics were assessed on the last day of each treatment (days 14 and 28 in arm 1 and days 6 and 20 in arm 2). The exposures C(max) and the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of saquinavir and ritonavir with or without ketoconazole were not substantially altered after 2 weeks of concomitant dosing with ketoconazole. The C(max) and AUC(0-12) of ketoconazole, dosed at 200 mg once daily, were increased by 45% (90% confidence interval = 32 to 59%) and 168% (90% confidence interval = 146 to 193%), respectively, after 2 weeks of concomitant dosing with ritonavir-boosted saquinavir (1,000 mg of saquinavir/100 mg of ritonavir given twice daily). The greater exposure to ketoconazole when given in combination with saquinavir/ritonavir was not associated with unacceptable safety or tolerability. No dose adjustment for saquinavir/ritonavir (1,000/100 mg twice daily) is required when coadministered with 200 mg of ketoconazole once daily, and high doses of ketoconazole (>200 mg/day) are not recommended.
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PMID:Drug-drug interaction study of ketoconazole and ritonavir-boosted saquinavir. 1901 29

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined ritonavir effects on stereoselective methadone pharmacokinetics and clinical effects (pupillary miosis) in healthy human immunodeficiency virus-negative volunteers. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone after no ritonavir, short-term (3-day) ritonavir, and steady-state ritonavir. Acute and steady-state ritonavir, respectively, caused 1.5- and 2-fold induction of systemic and apparent oral R- and S-methadone clearances. Ritonavir increased renal clearance 40-50%, and stereoselectively (S > R) increased hepatic methadone N-demethylation 50-80%, extraction twofold, and clearance twofold. Bioavailability was unchanged despite significant inhibition of intestinal P-glycoprotein. Intestinal and hepatic CYP3A was inhibited > 70%. Ritonavir shifted methadone plasma concentration-miosis curves leftward and upward. Rapid ritonavir induction of methadone clearance results from increased renal clearance and induced hepatic metabolism. Induction of methadone metabolism occurred despite profound CYP3A inhibition, suggesting no role for CYP3A in clinical methadone metabolism and clearance. Ritonavir may alter methadone pharmacodynamics.
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PMID:Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. 1923 55

Lopinavir, a human immunodeficiency virus protease inhibitor, has a very low oral bioavailability, which can be enhanced with a low dose of the CYPA4 inhibitor ritonavir. Our aim was to separately quantify the role of intestinal and hepatic cytochrome P450 3A (CYP3A4) expression on lopinavir disposition in a novel mouse model. Lopinavir and ritonavir were administered to mice selectively expressing human CYP3A4 in the intestine and/or liver. Using nonlinear mixed-effects modeling, we could separately quantify the effects of intestinal CYP3A4 expression, hepatic CYP3A4 expression, and the presence of ritonavir on both the absorption and elimination of lopinavir, which was previously not possible using noncompartmental methods. Intestinal, but not hepatic, CYP3A4-related first-pass metabolism was the major barrier for systemic entry of lopinavir. Relative oral bioavailability of lopinavir in mice expressing both hepatic and intestinal CYP3A4 was only 1.3% when compared with mice that were CYP3A deficient. In presence of ritonavir, relative bioavailability increased to 9.5% due to inhibiton of intestinal, but not due to inhibition of hepatic first-pass metabolism. Hepatic CYP3A4 related systemic clearance was inversely related to ritonavir exposure and not only hepatic but also intestinal CYP3A4 expression contributed to systemic clearance of lopinavir.
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PMID:An integrated pharmacokinetic model for the influence of CYP3A4 expression on the in vivo disposition of lopinavir and its modulation by ritonavir. 2149 55

Ritonavir (RTV) was used as a boosting agent to increase the clinical exposure of 11-ethyl-5,11-dihydro-5-methyl-8-[2-[(1-oxido-4-quinolinyl)oxy]ethyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (BILR 355), an inhibitor of the human immunodeficiency virus, by inhibiting the CYP3A-mediated metabolism of BILR 355. However, although the levels of BILR 355 increased upon concomitant administration of RTV, a metabolite of BILR 355, BILR 516, which was not detected previously in humans dosed with BILR 355 alone, became a disproportionate human metabolite with levels exceeding the parent levels at steady state. This was an unusual finding based on the in vitro and in vivo metabolic profiles of BILR 355 available at that time. Our studies reveal that BILR 355 is reduced to an intermediate, BILR 402, by gut bacteria and the reduced metabolite (BILR 402) is then oxidized by aldehyde oxidase to form BILR 516, the disproportionate human metabolite. The role of aldehyde oxidase helped to explain the somewhat unique formation of BILR 516 in humans compared with preclinical animal species. This article underlines the increasing importance of two individually atypical enzymes in drug development, gut bacterial biotransformation and aldehyde oxidase, which in combination provided a unique metabolic pathway. In addition, this article clearly elucidates an example of novel metabolic switching and, it is hoped, raises awareness of the potential for metabolic switching in combination drug therapies.
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PMID:Metabolic switching of BILR 355 in the presence of ritonavir. II. Uncovering novel contributions by gut bacteria and aldehyde oxidase. 2239 21

Human immunodeficiency virus (HIV) protease inhibitors (PIs) produce profound and unpredictable drug-drug interactions (DDIs) that cannot be explained fully by their inhibition/inactivation of CYP3A enzymes. Delineating and quantifying the CYPs and transporters inducible by PIs are crucial in developing an integrative mechanistic understanding and prediction of PI-based DDIs. To do so, two LC-MS/MS cocktail assays were modified and validated simultaneously to quantify the CYP activity of CYP3A, 2B6, 2C8, 2C9, 2C19, 1A, 2E1, 2A6 and 2D6 enzymes. These new assays were applied to evaluate the induction potential of eight PIs in microsomes isolated from PI-treated human hepatocytes. The mRNA expression of these CYPs and transporters (OATP1B1, OATP1B3, OATP1A2, MDR1, MRP2 and MRP4) was also evaluated using relative RT-PCR. The majority of PIs were net inducers of CYP3As and 2B6 at both the mRNA and activity level (> 2-fold), while ritonavir, saquinavir, nelfinavir or lopinavir did not induce CYP3A activity (< 2-fold), presumably due to CYP3A inactivation. OATP1B1 and MDR1 were the only two hepatic transporters induced (> 2-fold) by the PIs. Amprenavir was the most potent net inducer. In conclusion, our validated cocktail assays can be implemented to comprehensively quantify CYP activities in human liver microsomes and hepatocyte studies. The results also provide the much needed data on the net induction potential of the PIs for hepatic CYPs and transporters. A qualitative agreement was observed between our results and published PI-based DDIs, suggesting that human hepatocytes are a useful platform for more extensive and quantitative in vitro-in vivo prediction of PI-based DDIs.
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PMID:Quantification of human hepatocyte cytochrome P450 enzymes and transporters induced by HIV protease inhibitors using newly validated LC-MS/MS cocktail assays and RT-PCR. 2249 95

The protease inhibitor (PI) ritonavir is a potent inhibitor of cytochrome P450 (CYP) 3A4 activity and frequently prescribed to boost the effectiveness of other PIs as part of highly active antiretroviral therapy. It is well established that ritonavir is capable of inducing iatrogenic Cushing syndrome (ICS) through a drug-drug interaction with inhaled fluticasone that leads to the inhibition of CYP3A activity. A rapidly increasing number of case reports are being published describing ICS induced by the interaction of ritonavir and injected corticosteroids, namely triamcinolone acetonide. A review of the current literature identified 15 cases (including the one reported here) of ICS and suppression of the hypothalamic-pituitary-adrenal axis after periradicular injection of triamcinolone acetonide. Considering an aging human immunodeficiency virus (HIV)-infected population an increasing number of patients will present with degenerative musculoskeletal disease and be seeking pain relief. Based on data reported in the literature and our own experience triamcinolone injections during ritonavir-based therapy should be avoided. After failure of all conservative therapeutic options methylprednisolone may represent a therapeutic alternative for steroid injections in HIV patients receiving PI-based antiviral therapy since it has to date not been associated with ICS.
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PMID:Triamcinolone and ritonavir leading to drug-induced Cushing syndrome and adrenal suppression: description of a new case and review of the literature. 2387 67


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