We conclude that, first, rifabutin can enhance absorption (indicated by higher Cmax) of P-gp substrate victim drugs by inhibiting intestinal P-gp. This might be most important during the initial phase of combination therapy. Second, rifabutin is in fact an inducer of drug-metabolizing enzymes and drug transporters after repetitive administration, potentially leading to lowered victim drug exposure. However, P-gp inhibition can still overlap with (or even exceed) induction effects, especially when the victim drug and rifabutin (perpetrator) are administered simultaneously, leading to high intestinal rifabutin inhibitory drug concentrations. In general, we would also like to emphasize how important it is to complement empirical results with mechanistic analyses. In this regard, the important work of Kawuma and co-workers was a very valuable contribution.