The aims of this work were to study pharmacokinetics of randomly selected drugs in plasma and saliva samples in healthy human volunteers, and to introduce a Salivary Excretion Classification System. Saliva and plasma samples were collected for 3-5 half-life values of sitagliptin, cinacalcet, metformin, montelukast, tolterodine, hydrochlorothiazide (HCT), lornoxicam, azithromycin, diacerhein, rosuvastatin, cloxacillin, losartan and tamsulosin after oral dosing. Saliva and plasma pharmacokinetic parameters were calculated by noncompartmental analysis using the Kinetica program. Effective intestinal permeability (P(eff)) values were estimated by the Nelder-Mead algorithm of the Parameter Estimation module using the SimCYP program. P(eff) values were optimized to predict the actual average plasma profile of each drug. All other physicochemical factors were kept constant during the minimization processes. Sitagliptin, cinacalcet, metformin, tolterodine, HCT, azithromycin, rosuvastatin and cloxacillin had salivary excretion with correlation coefficients of 0.59-0.99 between saliva and plasma concentrations. On the other hand, montelukast, lornoxicam, diacerhein, losartan and tamsulosin showed no salivary excretion. Estimated P(eff) ranged 0.16-44.16 × 10(-4) cm/s, while reported fraction unbound to plasma proteins (fu) ranged 0.01-0.99 for the drugs under investigation. Saliva/plasma concentrations ratios ranged 0.11-13.4, in agreement with drug protein binding and permeability. A Salivary Excretion Classification System (SECS) was suggested based on drug high (H)/low (L) permeability and high (H)/low (L) fraction unbound to plasma proteins, which classifies drugs into 4 classes. Drugs that fall into class I (H/H), II (L/H) or III (H/L) are subjected to salivary excretion, while those falling into class IV (L/L) are not. Additional data from literature was also analyzed, and all results were in agreement with the suggested SECS. Moreover, a polynomial relationship with correlation coefficient of 0.99 is obtained between S* and C*, where S* and C* are saliva and concentration dimensionless numbers respectively. The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion. Future work is planned to test these initial findings, and demonstrate SECS robustness across a range of carefully selected (based on physicochemical properties) drugs that fall into classes I, II or III.