We review some pharmacokinetic principles that can facilitate interpretation of data obtained during therapeutic drug monitoring: the one- and two-compartment models, volume of drug distribution, drug clearance, organ clearance, bioavailability, first-pass effect, chronic or repetitive dosing, and use of urine and saliva to measure drug clearance and drug binding to plasma proteins, respectively. We also describe use of saliva to estimate rapidly, conveniently, and noninvasively the concentration of the free, pharmacologically active form of the drug as well as the fraction of drug bound to plasma protein.

The disposition of morphine was investigated by means of radioimmunoassay after a single intravenous dose (10 milligrams per 70 kilograms) was administered to 10 adult normal male subjects who had not received other drugs for 2 weeks preceding the study. A multiphasic decline in serum concentrations of morphine occurred. Detectable blood concentrations of morphine, or of a metabolite, or of both persisted for 48 hours after a single intravenous dose.

Plasma antipyrine half-lives exhibited an inverse relationship to hepatic microsomal aniline hydroxylase (r = –0.78) and ethylmorphine N-demethylase (r = –0.79) activities in healthy mongrel dogs. However, no close correlation occurred between plasma antipyrine half-life and hepatic microsomal cytochrome P-450 content (r = –0.07) cytochrome c reductase activity (r = –0.21) or NADPH oxidase activity (r = –0.30). In dogs retested at 21 days, plasma antipyrine half-life was a highly reproducible value in each animal. However, at shorter time intervals the dose of antipyrine used (75 mg/kg, i.v.) probably induced hepatic microsomal drug metabolism since retesting 10 days after the initial dose disclosed shortening of the plasma antipyrine half-life in each animal. These experiments suggest that under certain conditions plasma antipyrine half-lives may be useful indices of rates of hepatic metabolism of several compounds chemically unrelated to antipyrine.

Temporal variations in antipyrine disposition were studied in 19 normal male volunteers using salivary antipyrine half‐lives determined after a single oral dose of antipyrine (18 mg Ikg) given at 7:00 A.M. Specimens of saliva obtained at half‐hour intervals from 10:30 A.M. to 2:00 P.M. and also from 10:30 P.M. to 2:00 A.M. were designated the noon and midnight periods, respectively. In these 19 volunteers there were no significant differences between the mean antipyrine half‐lives calculated using only the noon period (12.8 ± 3.0 hr SD), those calculated using only the midnight period (13.2 ± 3.6 hr SD), and those determined using the whole 24‐hr period (13.0 ± 2.5 hr SD); neither were there significant differences among these periods for mean antipyrine metabolic clearance rates and mean apparent volumes of distribution. However, between the noon and midnight periods, 12 of the 19 subjects changed antipyrine half‐life by more than 10%. In the 12 subjects in whom the change exceeded 10%, there were 7 increases and 5 decreases in antipyrine half‐life. The range of extremes was more than 2‐fold, from an increase in half‐life of 173% in one individual to a decrease of 42% in another. That these temporal changes were not random fluctuation is suggested by repeated studies performed in the 5 subjects who exhibited the largest alterations; when the temporal change exceeded 10%, values were reproducible with respect to direction as well as magnitude. The observation that neither the direction nor the magnitude of temporal variation was altered by antipyrine administration at 7:00 P.M., rather than 7:00 A.M., also supports the concept that an endogenous circadian rhythm affects drug metabolism. Another rhythm, noted over a much shorter period of time, was a waver in the curves for both saliva and plasma antipyrine concentrations of all subjects. Since the same rhythm was also observed when antipyrine was measured in numerous aliquots of a single sample, the waver appeared to be artifactual in nature arising from random variability in the assay.