Biomedical subjects

M Gibaldi

Publications and source records attributed to M Gibaldi.

195 records · Page 11Linked to original sources

PubMedDate not supplied

Rapid estimation of chloramphenicol clearance in infants and children.

A method is presented by which chloramphenicol clearance (CL) can be estimated from a single serum sample obtained 6 hours after the initial intravenous dose. The method was evaluated prospectively in 20 infants and children who received intravenous chloramphenicol sodium succinate. Agreement between predicted and observed clearance was excellent (r = 0.914, p less than 0.001). The equation of the observed regression line was: observed 0.886x predicted + 0.019. The method appears to provide reasonably accurate estimates of clearance which can be used for rapid clinical adjustment of dose.

Child↗

PubMedDate not supplied

Influence of pharmacokinetic diurnal variation on bioavailability estimates.

The effects of diurnal variation on bioavailability assessments were examined using computer-simulated data based on the changes observed in theophylline kinetics. During one 12-hour dosage interval (noon to midnight), clearance was assumed to be larger than during the other dosage interval (midnight to noon). Oral data was simulated until steady-state occurred. Intravenous bolus data, which represented a stable-isotope pulse dose, was also simulated for both the high and low clearance dosage intervals. When the respective areas under the serum concentration-time curves were compared, the systemic availability (F = AUCpo/AUCiv) during the dosage interval with the larger clearance was greater than 1.0, but during the dosage interval with the smaller clearance it was less than 1.0. When computing the bioavailability of a drug, diurnal variations should be assessed as a potential cause of variation.

Biological Availability↗

PubMedDate not supplied

Characteristics of warfarin hydroxylation catalyzed by human liver microsomes.

The oxidative biotransformation of (R)- and (S)-warfarin was studied in human liver microsomes to determine whether an in vitro model could be established that would correspond to the in vivo profile that is generally observed. The quantitative pattern of oxidized products obtained from warfarin in vitro changed dramatically as a function of substrate concentration. Apparent Km values for the formation of 4', 6, 7, and 8-hydroxywarfarin indicated the presence of two easily distinguishable subsets of human liver cytochrome P-450; a high affinity subset (Km 3-15 microM) and a low affinity subset of isozymes (Km greater than 200 microM). The high affinity subset is primarily responsible for the metabolic profile of the biologically more potent (S)-enantiomer in vivo, whereas the low affinity subset is largely responsible for metabolism of the (R)-enantiomer. Apparent Vmax values alone did not reflect the relative in vivo formation clearances of the phenolic metabolites from either antipode, because the low affinity-high capacity component masked the metabolic profile of the (S)-enantiomer. However, the rank order of intrinsic clearance, Vmax/Km, for each metabolite was in good agreement with regio- and stereoselective metabolism in vivo. This investigation highlights the need for rigorous kinetic characterization of an in vitro model before reasonable correlation can be expected with in vivo data.

Humans↗

PubMedDate not supplied

Pharmacokinetic model of presystemic metabolism.

A pharmacokinetic perfusion model is presented that describes the disposition of drugs that are subject to both first-pass hepatic and intestinal epithelial metabolism. Equations are developed to estimate hepatic and intestinal epithelial clearances by determining drug concentrations as a function of time in both portal and peripheral vein blood after oral and iv administration, and by determining or estimating the flow rate of blood perfusing the gastrointestinal tissues. A method that can be used, under the stated conditions, to approximate the systemic availability after oral administration of drugs subject to presystemic metabolism is also developed.

Administration, Oral↗

PubMedDate not supplied

Prolonged impairment of the plasma-protein binding of phenytoin in the rat after a single dose of sodium oleate.

The plasma-protein binding of phenytoin in rats was impaired for more than 14 days after a single injection of sodium oleate compared to that observed in saline-treated controls. A maximum free (unbound) phenytoin fraction value of about 0.30 was found between 30 and 120 min after oleate administration. The free fraction decreased to about 0.20 after 14 days. The free fraction of phenytoin in control rats was essentially constant over this period and averaged about 0.17. The impaired plasma-protein binding of phenytoin was unaffected by prolonged dialysis but was effectively reversed by charcoal treatment of the plasma. Comparison of the in vivo and in vitro effects of sodium oleate on phenytoin binding in plasma indicates that the reduction in binding is unrelated to the in vivo oleate concentration in plasma at the time of the binding determination. For example, 5 min after a bolus injection of oleate, the plasma free fraction of phenytoin was about 0.33. A comparable concentration of oleate in control plasma resulted in a free phenytoin fraction of only 0.21.

Animals↗

PubMedDate not supplied

Pharmacokinetics of digoxin in the rat.

Previous studies on the pharmacokinetics of 3H-digoxin in the rat have been based on total radioactivity in the plasma, even though the drug is extensively metabolized in this species. A comparison of total radioactivity vs. unchanged drug in rat plasma after administration of 3H-digoxin clearly showed the need to separate digoxin from its metabolites. The pharmacokinetics of digoxin were therefore examined using solvent extraction and thin-layer chromatography to isolate unchanged drug. Digoxin levels after a 1 mg/kg iv dose were measured in the plasma and urine of adult male rats in which the bile duct or the ureters had been ligated, as well as in sham-operated controls. In all cases, digoxin concentrations were best described by a two-compartment open model. Digoxin was rapidly eliminated from the plasma of controls, with a half-life of 2.5 hr, a volume of distribution of 3.6 liter/kg, and a renal clearance somewhat lower than the glomerular filtration rate. No significant change in these parameters was observed in rats with bile duct ligation. The total body clearance of 5.77 ml/min in the controls was reduced by only 10% in the bile duct-ligated rats. In animals with bilateral ureter ligation, the body clearance was reduced by 30% and the plasma half-life of digoxin was increased to 4 hr, although no significant change in the apparent volume of distribution was noted. Approximately 60% of the total body clearance was unaffected by bile duct and ureter ligations, and was assumed to be due to biotransformation. Biliary excretion was found to be important for digoxigenin bisdigitoxoside, inasmuch as rats with bile duct ligation showed elevated metabolite levels in the plasma as well as a 3-fold increase in renal excretion of the bisglycoside.

Animals↗

PubMedDate not supplied