The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of phenobarbitone on human hepatic drug metabolism.

1. Single sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Clearance estimates were calculated in healthy young adult male volunteers either taking no pretreatment, or taking phenobarbitone (PB) 100 mg nightly for 3 nights. This intermittent regimen (3 nights on, followed by 4 nights off) was repeated for at least 3 consecutive weeks prior to challenge with an individual probe. 2. Valproic acid was selected as a probe of both peroxisomal and microsomal beta-oxidase activity; antipyrine, phenytoin, quinidine, and carbamazepine were selected as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyl transferase activity. 3. Clearances of all probes except lorazepam, theophylline and phenytoin were approximately 20-30% faster in PB-treated than in control subjects; however, only in the case of carbamazepine did the increased clearance approach statistical significance. Neither phenytoin nor theophylline clearances were increased by PB. 4. A clearance index (probe CL for PB-treated subjects divided by probe CL for untreated subjects) was calculated for each probe, and an ordinal transformation of the log of the resultant ratio was plotted for each probe giving rise to a 'handprint' of the effect of PB on drug-metabolizing activity.

Changes in the steady-state pharmacokinetics of theophylline during treatment with dirithromycin.

The steady-state plasma concentrations and pharmacokinetic characteristics of theophylline were studied during intermittent treatment with dirithromycin. The addition of dirithromycin (500 mg orally once daily at 7:00 AM) to a sustained-release theophylline dosing regimen (200 mg every 12 hours) elicited small changes in the steady-state pharmacokinetics of theophylline. Mean steady-state plasma theophylline trough concentrations (Cmin) were invariant before, during, and after dirithromycin treatment; however, mean average steady-state plasma theophylline concentrations (Cav) declined by 18% during dirithromycin treatment (P less than .05), and mean peak plasma concentrations (Css,max) declined by 26% (P less than .01). Theophylline clearance (CL/F) exhibited an increase of comparable magnitude during dirithromycin treatment, although the increase in CL/F was not statistically significant (.05 less than P less than .1). Dirithromycin treatment alters the steady-state pharmacokinetics of theophylline; however, the magnitude of the changes is small and is not likely to modify treatment outcomes.

Failure of ceftibuten to alter single dose theophylline clearance.

Twelve volunteers participated in a two-way crossover trial in which the effects of ceftibuten on the pharmacokinetics of theophylline were evaluated. Subjects were given single intravenous doses of theophylline (4 mg/kg) with no ceftibuten treatment and on the sixth day of ceftibuten treatment. Ceftibuten 200 mg was taken orally twice daily (7:00 AM and 7:00 PM). A total of 13 blood samples per subject were collected over 48 hours following theophylline administration. Ceftibuten failed to alter either the systemic clearance of theophylline (CL), its volume of distribution (Vss), or its elimination half-life (t1/2). The 24-hour plasma theophylline concentration measured both by high performance liquid chromatography (HPLC) or fluorescence polarization immunoassay (FPIA) was used for a single sample estimate of theophylline clearance (CL), and it was found to provide a suitable estimate of the multisample value for CL.

The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of cigarette smoking on human hepatic drug metabolism.

1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multiple-sample estimates of clearance for quinidine, valproic acid, unbound valproic acid, and lorazepam. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates, CL, corresponded closely to multiple-sample clearance estimates. Best post-dose sampling times were: quinidine, 8 h; valproic acid, 24 h; and lorazepam, 24 h. 2. Single-sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Valproic acid was used to probe microsomal and peroxisomal beta-oxidase activity; antipyrine, phenytoin, quinidine, carbamazepine, and theophylline were used as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely probe CL for smokers divided by probe CL for non-smokers) was calculated for each probe. The effect of cigarette smoking (and presumably polycyclic aromatic hydrocarbon exposure) on all probe CL values was consolidated and plotted as the logarithm of the CI to produce a handprint of drug metabolizing enzyme activity for cigarette smokers. 4. Only theophylline CL was significantly faster among smokers than non-smokers (P less than 0.01). 5. We conclude that the use of multiple probes of MFO activity when given in a single-dose, single-sample protocol for structuring handprints represents a minimally invasive and useful approach to characterize xenobiotic-mediated effects on hepatic MFO.