Saliva versus Plasma Pharmacokinetics: Theory and Application of a Salivary Excretion Classification System

Abstract

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.

Taste of a Pill

“…Drugs are known to be excreted into saliva, which represents the first step for taste disturbance induced by many medications. Sampling drug concentrations in saliva is clinically used in the assessment of therapeutic levels of drugs and the monitoring of illicit drug use (4,5). Nevertheless, very little is presently known regarding the molecular mechanisms underlying salivary secretion of drugs and other foreign chemicals.…”

“…As taste receptors are located in taste buds on the tongue, the physical presence of a drug substance in saliva is a prerequisite for taste disturbance caused by many medications. Drugs are known to be excreted into saliva; however, other than passive diffusion, the molecular mechanisms by which salivary gland epithelial cells secret xenobiotics are virtually unknown (4,5).…”

Quantitative mass spectrometry of unconventional human biological matrices

“…Typically, only solid particles are removed by centrifugation. In several studies, proteins were precipitated with small amounts of an organic solvent prior to analysis of low-molecular-weight drugs [38,70]. In addition, SPE may be performed to preconcentrate and purify the analytes [69].…”

Saliva vs. Plasma Bioequivalence of Paracetamol in Humans: Validation of Class I Drugs of the Salivary Excretion Classification System

“…Class III drugs of high intestinal permeability and high protein binding, such as cinacalcet, are subjected to salivary excretion since high protein binding is counterbalanced by high permeability. Class IV drugs of low intestinal permeability and high protein binding, such as montelukast, are not subjected to salivary excretion [ 3 ] .…”

“…Saliva sampling off ers simple, non-invasive and cheap method as compared with plasma sampling with no contamination risk, yet needs special attention that no drug residue is left in the mouth after dosing [ 1 , 2 ] . In addition, drug analysis in the clean saliva matrix is simple and can be done using same method of analysis as plasma matrix [ 3 ] . The rules of drug protein binding and membrane permeability on salivary excretion were previously investigated for several drugs, where a Salivary Excretion Classifi cation System (SECS) proposed as shown in • ▶ Table 1 [ 3 ] .…”