To study the potential interactions of naringin (NAR), talinolol (TAL) and protein-energy undernutrition (PEU) in the absorption process of saquinavir (SQV), perfusion experiments were performed in the small intestine of rats at different SQV concentrations. The results obtained demonstrated that SQV intestinal absorption was described by simultaneous passive diffusion (k(dif) = 3.44 hr) and saturable absorption (V(ma) = 127.31 μM/hr; K(ma) = 10.50 μM) together with a capacity-limited efflux (V(ms) = 270.53 μM/hr; K(ms) = 23.44 μM). The competitive inhibition constants of NAR on the SQV input and efflux processes were [IC50](a) = 3.98 μM and [IC50](s) = 5.00 μM, respectively. NAR significantly decreased (23-29%; p < 0.05) or kept unaltered the absorption rate constant (k(a) ) of SQV in function of the concentration of both compounds administered. Finally, SQV k(a) significantly increased in PEU status (around 1.8 times) when the drug was perfused either in the presence (p < 0.05) or in the absence (p < 0.01) of NAR. The variations of SQV k(a) when the antiretroviral drug is co-administered with NAR and/or TAL reinforce their interaction in the absorptive process. Malnutrition may result in altered SQV absorption, and further studies are strongly recommended to analyse the impact of this finding on the pharmacokinetic drug profile.