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Positive Correlation between Indinavir and Retinoic Acid Effects in Mice J. LENHARD*, D. CROOM, J. BINZ, and R. JAIN.
Glaxo Wellcome Inc., Res. Triangle Park, NC Objective: Unlike other HIV-protesase inhibitor, indinavir (IDV) increases all-trans-retinoic acid (ATRA, vitamin A acid) signalling in vitro. To determine if IDV causes retinoid-like effects in vivo, the response to IDV or ATRA treatment was compared using controlled conditions in mice.
Methods: AKR/J mice were treated for two weeks with indinavir (2.9 mg/d) or ATRA (1.2 mg/d) by subcutaneous infusion. Eighteen measurements were recorded, including the serum concentrations of glucose, insulin, lipase, leptin, blood lipids, and several clinical toxicology markers.
Results: IDV and ATRA treated mice had significantly greater serum levels of triglycerides, free fatty acids, glycerol, and alkaline phosphatase and less weight gain than control mice (P<0.03). Unlike ATRA, IDV treatment significantly increased serum levels of bilirubin, hydroxybutyric acid, and cholesterol (P<0.04). Additionally, ATRA treated mice had greater insulin, C-peptide, pancreatic lipase, and insulin resistance than control mice (P<0.01). Although indinavir treatment did not have a significant effect on these parameters (P>0.05), the mean levels of insulin, C-peptide, pancreatic lipase, glucose, and insulin resistance were greater in the IDV than the control animals. Regression analysis revealed a correlation coefficient of 0.73 (P = 0.0005) between the adverse reactions in the IDV and ATRA treated mice.
Conclusion: The results show IDV and ATRA cause similar side effects in mice. Although it is possible that IDV and ATRA do not interact with all of the same proteins, these drugs may bind to one or more common proteins (such as cytosolic retinoic acid binding protein, CRABP) accounting for some of their similar effects in vivo.
Key Words: Indinavir, Metabolism, Retinoic Acid
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