Garlic phytochemicals and garlic supplements influence the pharmacokinetic and pharmacodynamic behavior of concomitantly ingested drugs. In this paper we have summarized the mechanisms responsible for first-pass intestinal pharmacokinetic interactions by investigating the intestinal permeability of some cardiovascular, antiviral drugs, their transport with hepatic transporters and CYP3A4 metabolism. Transporter-enzyme interplay was studied with several in vitro models of varying complexity: rat small intestine and Caco-2 cell monolayers were used in studies of intestinal processes, and hepatic pharmacokinetics was monitored in HepG2 cells, isolated rat hepatocytes and rat liver slices. Garlic phytochemicals from aged garlic extract modified the activities of secretory and absorptive transporters in both intestine and liver and competitively inhibited CYP3A4 enzyme. The increased activities of the most important intestinal efflux (P-glycoprotein - Pgp, Multidrug Resistance Associated Protein 2 - MRP-2, Breast Cancer Resistance Protein - BCRP) and uptake (MonoCarboxylate Transporter 1 - MCT1, Organic Anion Transporting Polypeptide - OATP, Peptide transporter 1 - PepT1) transporters were caused by changes in electrophysiological membrane properties and by allosteric modifications. Because clinical studies investigating interactions between garlic and human immunodeficiency virus protease inhibitors saquinavir and ritonavir have already been performed, we used these in vivo data to evaluate the in vitro results and the reliability of the models employed as screening tools for forecasting the potential of first-pass intestinal metabolism changes. We also assessed the probability of pharmacokinetic interactions with garlic of the novel drug darunavir and other cardiovascular drugs. Finally, selected garlic phytochemicals were tested for their ability to influence P-glycoprotein and CYP3A4 activities.