Movement of drugs into saliva
Henderson–Hasselbalch equation
At equilibrium, the drug and lipophilic metabolite concentrations in saliva are a function of the drug’s pKa, plasma and saliva pH, and the fraction of drug bound to saliva and plasma protein, as Shown by the form of the Henderson–Hasselbalch equation for saliva:
S/P, the saliva to plasma ratio, for basic drugs is
where S is the drug concentration in saliva, P is the drug concentration in plasma, pKd is the log of the ionisation constant for basic drugs, pKa is the log ionisation constant for acidic drugs, pHs is the pH of saliva, pHp is the pH of the plasma, fp is the fraction of drug protein bound in plasma and fs is the fraction protein bound in saliva. The pH that governs this equilibrium is the pH of the saliva in the acinar lumen and in the duct at the moment of secretion. When the fluid enters the mouth, carbon dioxide is lost and the pH increases. Dawes and Jenkins (1964) demon strated that saliva pH is inversely proportional to flow rate and the reabsorption of sodium in the salivary tubules. At faster flow rates, less sodium is reabsorbed in the tubules on the way from the saliva glands to the saliva outlets in the mouth, and the pH rises. For this reason, unstimulated saliva has a low pH (at low flow rates it is between 6.0 and 7.0, and fairly constant) and stimulated saliva has a higher pH (it can reach as high as 8.0). Since human saliva normally has a lower pH than human plasma, the saliva: plasma ratios for acid drugs are generally less than unity and the saliva: plasma ratios for basic drugs are greater than unity, which provides an amplification of basic drug levels in saliva. For drugs that have a pKa between 5.5 and 8.5, the saliva: plasma ratio can vary between stimulated and unstimulated saliva. This is true of many drugs of abuse. For this reason, it is more conservative to use a cut-off value for drugs of abuse in saliva rather than to determine the absolute concentration. The most common example given is that of cocaine, which has a pKa of 8.6 (Schramm et al. 1992; Haeckel 1993). As the saliva pH varies from 5.0 to 7.8, the saliva: plasma ratio for cocaine varies from 273 to 0.44. The theoretical ranges of saliva: plasma ratios over a saliva pH range of 6.4 to 7.6 have been calculated for cocaine, amfetamine, methamfetamine, 6-MAM, morphine, codeine, methadone and diazepam and compared with published saliva: plasma ratios (Spiehler et al. 2000).
The protein binding of drugs is mainly to albumin or a-acid glycoprotein in plasma. Saliva mucoproteins have very little binding capacity for drugs. Oral fluids may contain albumin from the gingival crevicular fluid.
