The Protease Inhibitors Ritonavir and Saquinavir Influence Lipid Metabolism: A Pig Model for the Rapid Evaluation of New Drugs

@article{Petersen2010ThePI,
  title={The Protease Inhibitors Ritonavir and Saquinavir Influence Lipid Metabolism: A Pig Model for the Rapid Evaluation of New Drugs},
  author={Eskild Petersen and Huiling Mu and Trine Porsgaard and Lone S. Bertelsen},
  journal={Antiviral Therapy},
  year={2010},
  volume={15},
  pages={243 - 251}
}
Background Studies of the effects of antiretroviral drugs on lipid metabolism are limited by the availability of suitable models. We have thus developed an animal model utilising Göttingen mini-pigs. The normal lipid metabolism of mini-pigs closely reflects that of humans and they are expected to have similar reactions to antiretroviral drugs. Methods The pigs were treated orally with high doses of the protease inhibitors ritonavir and saquinavir for 4 weeks. The model allows repeated… 
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Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects

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Pathogenesis of lipodystrophy and lipid abnormalities in patients taking antiretroviral therapy.

What is known of the molecular mechanisms underlying HIV-associated lipodystrophy is summarized and a greater understanding of these mechanisms is essential if effective therapeutic options are to be found.

The Role of Protease Inhibitors in the Pathogenesis of HIV-Associated Lipodystrophy: Cellular Mechanisms and Clinical Implications

Both chronic inflammation from HIV infection and treatment with some drugs in this class trigger cellular homeostatic stress responses with adverse effects on intermediary metabolism, which leads to a pathologic cycle of lipotoxicity and lipoatrophy.

The HIV protease inhibitor saquinavir impairs lipid metabolism and glucose transport in cultured adipocytes.

It is suggested that some HIV protease inhibitors have direct effects on lipid and glucose metabolism and this inhibition of lipogenesis and glucose transport may explain some of the lipodystrophy, dyslipidemia and disturbed glucose metabolism with the clinical use of these drugs.

Protease inhibitor plasma concentrations in HIV antiretroviral therapy.

It is shown that it is feasible to measure protease inhibitors plasma concentrations in a clinical setting with precision and accuracy, and that protease inhibitor concentrations are very stable during different circumstances ex vivo.

Effects of boosted tipranavir and lopinavir on body composition, insulin sensitivity and adipocytokines in antiretroviral-naive adults

TPV/ r or LPV/r with tenofovir-lamivudine increased subcutaneous fat without evidence for increasing visceral fat or insulin resistance over 48 weeks, unlike many other antiretroviral regimens.

HIV Replication Enhances Production of Free Fatty Acids, Low Density Lipoproteins and Many Key Proteins Involved in Lipid Metabolism: A Proteomics Study

It is concluded that HIV replication alone, without any influence of antiviral drugs, or other human genetic factors, can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism.

HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options.

There is a need to explore alternative therapeutic options for combating Lipodystrophy, including adipocytokines, uridine supplementation, glitazones, growth hormone, metformin and statins (used alone or in combination) merit further investigation.

r-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans.

The effects of r-metHuLeptin in patients with HAART-MS are not mediated through increasing IGF or IGFBP levels, and there was no change in IGF1, IGF2, free IGF 1, or IGF-binding proteins during the 2-month treatment period.

Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects

Constant concentration-dependent autoinduction is the most likely mechanism for the time-dependent pharmacokinetics of ritonavir, and the levels were correlated with baseline triglyceride levels and AUC, Cmax, or predose concentrations.