Pharmacokinetic Interactions between Nelfinavir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Simvastatin

Hsyu, Poe‐Hirr; Schultz-Smith, Melissa D.; Lillibridge, James H.; Lewis, Reina; Kerr, Bradley M.

doi:10.1128/aac.45.12.3445-3450.2001

Cited by 130 publications

(59 citation statements)

References 25 publications

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“…39 Co-administration of simvastatin and lovastatin with protease inhibitors may significantly increase serum levels of the statin, resulting in potential myopathy, including rhabdomyolysis. 40,41 In contrast to the results of our study, the Swiss HIV Cohort Study found that only 2 % of their patients had been prescribed contraindicated ARV/non-ARV combinations, which largely involved midazolam, 35 while 59 % had been prescribed ARV/ non-ARV combinations that were not contraindicated, yet had interactions requiring potential dose adjustment and/or close monitoring. The differences between our observations and those of the Swiss HIV Cohort Study scientists may be explained at least in part by their use of a customized version of the Liverpool database, use of different definitions for important but not contraindicated interactions, and their review of all interactions by two pharmacists.…”

Section: Discussioncontrasting

confidence: 53%

Polypharmacy and Risk of Antiretroviral Drug Interactions Among the Aging HIV-Infected Population

et al. 2013

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BACKGROUND: Among aging HIV-infected adults, polypharmacy and its consequences have not been welldescribed. OBJECTIVE: To characterize the extent of polypharmacy and the risk of antiretroviral (ARV) drug interactions among persons of different ages. DESIGN AND PARTICIPANTS: Cross-sectional analysis among patients within the HIV Outpatient Study (HOPS) cohort who were prescribed ARVs during 2006-2010. MAIN MEASURES: We used the University of Liverpool HIV drug interactions database to identify ARV/non-ARV interactions with potential for clinical significance. KEY RESULTS: Of 3,810 patients analyzed (median age 46 years, 34 % ≥ 50 years old) at midpoint of observation, 1,494 (39 %) patients were prescribed ≥ 5 non-ARV medications: 706 (54 %) of 1,312 patients ≥ 50 years old compared with 788 (32 %) of 2,498 patients < 50 years. During the five-year period, the number of patients who were prescribed at least one ARV/non-ARV combination that was contraindicated or had moderate or high evidence of interaction was 267 (7 %) and 1,267 (33 %), respectively. Variables independently associated with having been prescribed a contraindicated ARV/non-ARV combination included older age (adjusted odds ratio [aOR] per 10 years of age 1.17, 95 % CI 1.01-1.35), anxiety (aOR 1.78, 95 % CI 1.32-2.40), dyslipidemia (aOR 1.96, 95 % CI 1.28-2.99), higher daily non-ARV medication burden (aOR 1.13, 95 % CI 1.10-1.17), and having been prescribed a protease inhibitor (aOR 2.10, 95 % CI 1.59-2.76). Compared with patients < 50 years, older patients were more likely to have been prescribed an ARV/non-ARV combination that was contraindicated (unadjusted OR 1.44, 95 % CI 1.14-1.82), or had moderate or high evidence of interaction (unadjusted OR 1.29, 95 % CI 1.15-1.44). CONCLUSIONS: A substantial percentage of patients were prescribed at least one ARV/non-ARV combination that was contraindicated or had potential for a clinically significant interaction. As HIV-infected patients age and experience multiple comorbidities, systematic reviews of current medications by providers may reduce risk of such exposures.

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Section: Discussioncontrasting

confidence: 53%

Polypharmacy and Risk of Antiretroviral Drug Interactions Among the Aging HIV-Infected Population

et al. 2013

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“…To counter this, statins are often administered to these individuals to reduce cholesterol and triglyceride levels (42). However, coadministration of retroviral protease inhibitor and statins has now been shown to increase several fold the peak concentrations of statins in the plasma (43)(44)(45). Whether this abnormally high concentration of statins in the plasma of HIV patients will result in any inflammatory response is not known and deserves further attention.…”

Section: Discussionmentioning

confidence: 99%

Statin-Induced Proinflammatory Response in Mitogen-Activated Peripheral Blood Mononuclear Cells through the Activation of Caspase-1 and IL-18 Secretion in Monocytes

Coward

Marei

Yang

et al. 2006

The Journal of Immunology

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Statins, which inhibit 3-hydroxy-3-methylglutaryl CoA reductase, have been shown recently to promote proinflammatory responses. We show in this study that both atorvastatin and simvastatin induced proinflammatory responses in mitogen-activated PBMCs by increasing the number of T cells secreting IFN-γ. This is abolished by the presence of mevalonate, suggesting that statins act specifically by blocking the mevalonate pathway for cholesterol synthesis to promote the proinflammatory response. Both statins at low concentrations induced a dose-dependent increase in the number of IFN-γ-secreting T cells in mitogen-activated PBMCs, whereas at higher concentrations the effect was abolished. The proinflammatory effect of statins was not seen in purified T cells per se activated with mitogen. However, conditioned medium derived from statin-treated PBMCs enhanced the number of IFN-γ-secreting cells in activated purified T cells. This effect was not blocked by mevalonate, but was abolished by neutralizing Abs to IL-18 and IL-12. Similarly, the up-regulation of IFN-γ-secreting T cells in PBMCs costimulated with statins and mitogens was blocked by the neutralizing anti-IL-18 and anti-IL-12. We showed that simvastatin stimulates the secretion of IL-18 and IL-1β in monocytes. Active caspase-1, which is required for the processing and secretion of IL-18 and IL-1β, was activated in simvastatin-treated monocytes. This was blocked by mevalonate and the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone. Taken together, the proinflammatory response mediated by statins in activated PBMCs is mediated mainly via the activation of caspase-1 and IL-18 secretion in the monocytes and to a lesser extent by IL-12.

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“…This interindividual variability may be caused by the fact that atorvastatin is supposed to inhibit HMG-CoA reductase in the liver, so the systemic levels of this lipophilic compound vary considerably between individuals. 12 Extending our data to the clinical situation, the differential response of the volunteers suggests that individual patients will benefit to different degrees from the pleiotropic effects of statins, independently of the lipid-lowering effect. The increase in nonisoprenylated inactive form of RhoA in PBMCs has been linked to the atheroprotective effects of statins on these cells, such as downregulation of plasminogen activator inhibitor-1 synthesis, 18 decreased transcription of matrix metalloproteinases and adhesion molecules in monocytes, 16 decreased monocyte-endothelial cell interactions, 23 and inhibition of activation and proliferation of T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Monitoring the Cellular Effects of HMG-CoA Reductase Inhibitors In Vitro and Ex Vivo

Cicha

Schneiderhan‐Marra

Yılmaz

et al. 2004

ATVB

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Objective-Inhibition of 3hydroxy3methylglutaryl-coenzyme A (HMG-CoA) reductase by statins and the subsequent reduction in Rho protein isoprenylation inactivates these important signaling molecules. The purpose of this study was to directly monitor statin effects on Rho proteins. Methods and Results-We used biphasic Triton X-114 system, 1-dimensional isoelectric focusing, and 2D-electrophoresis for the separation of modified and nonmodified Rho proteins. These methods were evaluated in human fibroblasts treated with simvastatin. 2D-electrophoresis, which proved to be the most sensitive method, revealed 2 major spots of identical molecular weight but different isoelectric points, with the more basic spot representing the carboxymethylated form of RhoA. In control cells, 90% of RhoA was fully modified (carboxymethylated). After treatment with simvastatin, a significant shift toward the unmethylated form was observed, representing inhibition of isoprenylation, which is a prerequisite to further modification. Similar shifts were observed for Rac1 and Cdc42. In freshly isolated peripheral blood mononuclear cells, a shift toward nonmodified RhoA was observed after treatment with atorvastatin in vitro and in vivo. There was a significant increase in unmethylated RhoA in statin-treated individuals versus control individuals. Key Words: RhoA Ⅲ isoprenylation Ⅲ carboxymethylation Ⅲ HMG-CoA reductase Ⅲ statins T herapy with 3hydroxy3methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) is associated with lipid-lowering and plaque-stabilizing effects, resulting from their interference with cholesterol biosynthesis. However, recent experimental and clinical evidence indicate that the beneficial effects of statins extend beyond cholesterol reduction, involving improved plaque composition, decreased inflammation, and ameliorated endothelial function. 1,2 These pleiotropic effects are mediated by the ability of statins to interfere directly with the posttranslational modification of signaling proteins, particularly small GTP-binding proteins of the Ras and Rho families. Because the membrane localization and function of Ras and Rho depend on the attachment of isoprenoid intermediates to these proteins, by inhibiting protein isoprenylation, statin treatment leads to accumulation of the inactive forms of Ras and Rho in the cytoplasm. Although farnesylation of Ras proteins and geranylgeranylation of Rho proteins are equally affected by statins, many of the beneficial cardiovascular effects of statins are thought to be a result of their interference with Rho protein signaling. 3 As interference with the geranylgeranyl modification of Rho proteins is one of the earliest steps related to the direct cellular actions of statins, it appears desirable to determine the relative amount of modified versus nonmodified protein. Some of the isoprenylated proteins, such as Ras proteins, can be separated from their nonmodified form by high-resolution SDS-polyacrylamide gel electrophoresis (SDS-PAGE). 4 However, for Rho family prot...

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Pharmacokinetic Interactions between Nelfinavir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Simvastatin

Cited by 130 publications

References 25 publications

Polypharmacy and Risk of Antiretroviral Drug Interactions Among the Aging HIV-Infected Population

Polypharmacy and Risk of Antiretroviral Drug Interactions Among the Aging HIV-Infected Population

Statin-Induced Proinflammatory Response in Mitogen-Activated Peripheral Blood Mononuclear Cells through the Activation of Caspase-1 and IL-18 Secretion in Monocytes

Monitoring the Cellular Effects of HMG-CoA Reductase Inhibitors In Vitro and Ex Vivo

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