Liver transcriptomic changes associated with ritonavir-induced hyperlipidemia in sensitive and resistant strains of rats.

Ritonavir (RTV) and other protease inhibitors (PIs) used for the treatment of human immunodeficiency virus (HIV) infection are associated with elevated serum triglycerides (TG) and cholesterol in some patients. A rat strain (Sprague–Dawley or SD) commonly used in toxicology studies is not sensitive to RTV-induced hyperlipidemia, making mechanistic studies and the identification of novel, lipid-neutral PIs challenging. The objective of this study was to identify a rat strain that mirrors human PI-associated hyperlipidemia. RTV was administered at 100mg/kg/day for 5days to a panel of 14 rat strains estimated to cover approximately 86% of the known genetic variance in rats. Increased serum TG and cholesterol levels occurred only in two rat strains, including LEW×BN rats. Livers from LEW×BN (sensitive) and SD (resistant) rats were then evaluated using microarrays to investigate differences in the transcriptomic response to RTV.