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Biomedical subjects

M Gibaldi

Publications and source records attributed to M Gibaldi.

At least 55 records · Page 3Linked to original sources
PubMed1983

Volume of distribution terms for a drug (ceftriaxone) exhibiting concentration-dependent protein binding. I. Theoretical considerations.

We have theoretically examined the influence of plasma protein binding (specifically the fraction unbound, fp) on the pharmacokinetic parameters following rapid injection of a drug undergoing concentration-dependent binding. Particular emphasis was placed on the apparent volume of distribution terms based on both total and unbound drug concentrations. Computer simulations were performed to establish the validity and utility of such relationships. The following observations were made: a) distributional parameters based on total drug (both V beta and the model-independent VSS) were inaccurate/invalid; b) V beta based on unbound drug was misleading; c) the model-independent VSS for unbound drug accurately predicted the steady state situation. Furthermore, two new terms (-fp and V-TSS) were introduced which provide additional insight concerning the disposition of this type of drug. The -fp is the area-weighted average fraction unbound in the plasma and V-TSS is the corrected steady state distribution term for total drug levels. The present study indicates that useful distributional and clearance terms can be calculated for this type of drug, provided that the time course of unbound drug as well as total drug can be followed. Moreover, guidelines for their extrapolation to steady state conditions and their correct interpretations are discussed.

Blood Proteins↗
PubMed1983

Volume of distribution terms for a drug (ceftriaxone) exhibiting concentration-dependent protein binding. II. Physiological significance.

Guidelines presented previously for the analysis of plasma concentration versus time data for a drug exhibiting concentration-dependent plasma protein binding were successfully applied to the distributional parameters of a new cephalosporin, ceftriaxone. This approach provided several striking observations when the pharmacokinetics of ceftriaxone in a healthy and uremic population were re-examined. First, the parameter -fp converted the apparent dose-dependent distributional terms of ceftriaxone into a function of the concentration-dependent plasma protein binding. Second, a strong correlation between the term VUSS and the reciprocal of -fp was established within each of the two populations. While this -fp term accounted for the variability within the respective populations due to ceftriaxone-albumin binding differences, it did not account for all of the distributional differences between the two populations. The present analysis revealed that the altered physiologic state of uremia (larger plasma volumes and interstitial to intravascular albumin ratios), in addition to differences in plasma protein binding, dictated the distribution of ceftriaxone in healthy and uremic subjects. Furthermore, the binding-disposition model which accounts for the presence of plasma proteins outside the vascular space, was established to be appropriate in describing the distribution of ceftriaxone.

Blood Proteins↗
PubMed1982

Pharmacokinetics of erythromycin in normal and alcoholic liver disease subjects.

The objective of this study was to compare the pharmacokinetic behavior of erythromycin in normal volunteers with that in subjects with alcoholic liver disease. Six normal volunteers received 500 mg erythromycin as an intravenous infusion or as two 250-mg enteric-coated tablets in a crossover fashion. The pharmacokinetics of erythromycin after intravenous administration was best described as a two-compartment model. The elimination half-life was 1.6 +/- 0.7 hours (mean +/- S.D.) after the intravenous dose and 2.0 +/- 0.7 hours after the oral dose. In patients with alcoholic liver disease the elimination half-life after oral administration of two 250-mg enteric-coated tablets was 3.2 +/- 0.5 hours, significantly different from that in normal subjects, probably due to impaired metabolism. The difference in half-life does not require dosage adjustment in this patient population. The systemic availability of erythromycin was 33.5 per cent (range 10.5 to 79.3 per cent).

Administration, Oral↗
PubMed1982

Estimation of statistical moments and steady-state volume of distribution for a drug given by intravenous infusion.

Although it is generally recognized that estimates of the area under the drug concentration vs. time curve (AUC) after a dose is rather insensitive to curve-fitting procedures, little is known about estimates of mean residence time (MRT) or volume of distribution at steady-state (Vss), both of which can be derived from area estimates. This question is of particular concern when a drug is given as a short-term constant rate i.v. infusion since the infusion phase is often ignored and blood sampling restricted to the postinfusion period. Two nonexperimental methods for approximating concentration data during infusion termed the linear approximation method and the imaginary bolus method were found to be useful under certain conditions. Both methods provide reasonable estimates of AUC and the area under the first moment of the drug concentration-time curve (AUMC) for drugs with a wide range of pharmacokinetic characteristics. The imaginary bolus method was found to be the better of the two for estimation of MRT and to be widely applicable for this purpose. Vss proved to be highly sensitive to the approximation methods; although the imaginary bolus method is superior to the linear approximation method for estimating Vss, it does not work particularly well for drugs with pronounced multicompartment characteristics. In general, accurate estimation of Vss of drugs given by short-term i.v. infusion requires that at least one drug concentration be determined during infusion.

Infusions, Parenteral↗
PubMed1982

Influence of long-term infusions on lidocaine kinetics.

Lidocaine kinetics were examined during continuous infusions in five healthy subjects using stable isotope lidocaine labeled with two deuterium atoms. During phase 1, lidocaine and stable isotope lidocaine (50 mg IV each) were given as a bolus to confirm that the two species were kinetically identical. Phase 2 consisted of a long-term (30 hr) lidocaine infusion designed to produce a steady-state concentration equal to 1.5 microgram/ml. Twenty-four hours into the infusion, stable isotope lidocaine (50 mg) was given as an intravenous bolus and kinetic parameters were calculated. Phase 3 differed from phase 2 in that target steady-state lidocaine concentration was 4 microgram/ml and the stable isotope lidocaine dose was reduced to 40 mg. A gas chromatograph-mass spectrometer was used to determine lidocaine and stable isotope lidocaine serum concentrations. Compared to phase 1, clearance decreased (P less than 0.05) and half-life increased (P less than 0.025) during phases 2 and 3. The volume of distribution at steady-state remained constant during all three phases. Lidocaine cumulated in serum during long-term infusions in all five patients; repeated decreases in infusion rate were necessary to avoid exceeding desired target concentrations in phases 2 and 3.

Adult↗
PubMed1982

Individualization of theophylline dosage using a single serum sample following a test dose.

Because formulas for theophylline requirement based on weight alone carry the risk of overdosing and toxicity, this study was designed to test a clearance nomogram for determining daily theophylline requirement after a known initial dose of theophylline. Twenty asthmatic children who had not taken theophylline for at least 36 hours fasted and were given one dose of anhydrous theophylline (5 mg/kg). Six hours later the serum level was measured and the appropriate dosage of sustained-release theophylline to achieve a serum level of 10 micrograms/ml was selected from the clearance nomogram. Three to seven days later a six-hour theophylline level was obtained. Of 20 patients, therapeutic levels of 10 to 30 micrograms/ml were achieved in 15, and the remaining five patients had levels close to this (range 6.2 to 16.0 micrograms/ml). The dosage requirement per 24 hours ranged from 10 to 32 mg/kg/24 hr. This method of determining theophylline requirements for children required measurement of the serum theophylline level only once for the determination of a safe and effective daily dose. It is especially valuable when follow-up is difficult and is a safe way to avoid serious overdosing while being certain of effective dosing.

Asthma↗
PubMed1981

Pharmacokinetic concepts - drug binding, apparent volume of distribution and clearance.

Blood flow rate-limited physiological pharmacokinetic models have been used to examine the relationship between apparent volume of distribution and clearance or, more specifically between drug binding in blood, eliminating regions or noneliminating regions and clearance. The influence of binding on drug elimination depends on the driving force concentration in the eliminating region. In most instances this is likely to be free drug concentration in the region. Under these conditions, the results indicate that apparent volume of distribution and drug clearance from the blood should be treated as independent pharmacokinetic variables. Volume of distribution per se has no effect on clearance or on average steady-state blood levels. Drug binding in nonvascular regions(i.e. tissue binding) seems to be of limited importance except as a determinant of half-life. Although changes in tissue binding will affect partition coefficient and apparent volume of distribution, such changes will have no effect on average steady-state blood levels of either total or free drug.

Computers↗
PubMed1981

Single point estimation of phenytoin dosing requirement.

Computer simulation demonstrated that a single serum sample obtained 24 hours after an intravenous loading dose of phenytoin (18 mg/Kg) can, with reasonable accuracy, predict the maintenance dose of phenytoin required to maintain a steady state serum concentration of 15 mg/L. A strong linear correlation (r = 0.959) was found between required phenytoin maintenance dose and the reciprocal of the 24 hour serum concentration.

Humans↗
PubMed1981

Endogenous accumulation products and serum protein binding in uremia.

A number of compounds known to accumulate in the blood of uremic patients were added to serum from healthy normal volunteers. It was observed that both hippuric acid and indican were capable of increasing substantially the serum f of both diazepam and warfarin. Furthermore, a mixture of nine different accumulation products (many of which did not measurably increase f when added alone) caused an even greater increase in the f of diazepam. Serum from uremic patients and from normal volunteers, with and without the addition of the compounds known to accumulate in uremia, wee treated by standard procedures (i.e., prolonged dialysis, charcoal treatment, pH alteration) to remove associated small molecules. The results of such treatments suggest that at least part of the diminished binding of drugs seen in the presence of uremia is due to the accumulation of low-molecular-weight endogenous competitors.

Blood Proteins↗
PubMed1981

Single point estimation of phenytoin dosing: a reappraisal.

A previously proposed method for estimation of phenytoin dosing requirement using a single serum sample obtained 24 hours after intravenous loading dose (18 mg/Kg) has been re-evaluated. Using more realistic values for the volume of distribution of phenytoin (0.4 to 1.2 L/Kg), simulations indicate that the proposed method will fail to consistently predict dosage requirements. Additional simulations indicate that two samples obtained during the 24 hour interval following the iv loading dose could be used to more reliably predict phenytoin dose requirement. Because of the nonlinear relationship which exists between phenytoin dose administration rate (RO) and the mean steady state serum concentration (CSS), small errors in prediction of the required RO result in much larger errors in CSS.

Humans↗
PubMed1980

Tissue distribution kinetics of tetraethylammonium ion in the rat.

Tissue distribution kinetics of tetraethylammonium (TEA) ion in rats were studied following both constant-rate intravenous infusion and rapid intravenous injection of the drug. At a steady-state plasma concentration of 0.2 microgram/ml, the tissue-to-plasma (T/P) concentration ratio of the kidneys, liver, heart, gut, and lungs exceeded 1, indicating that TEA is localized in these tissues. In vitro tissue homogenate binding and slice uptake experiments provided no evidence of TEA binding to tissue constitutents, suggesting that the high T/P concentration gradient is due to an active transport process. The maximum concentration of TEA in all tissues occured with 5-15 min after rapid injection of a 2-mg dose. Except for the liver, the subsequent decline of TEA concentration in various tissues over a 5-hr period was slow compared to that in plasma. Consequently, the T/P ratio of liver and kidney remained relatively constant, while those of the other tissues increased continually with time. These features of TEA tissue distribution kinetics can be predicted by a physiologically based pharmacokinetic model which incorporates both active and passive transport processes for the passage of TEA between blood and the tissue mass.

Animals↗
PubMed1980

Nonlinear pharmacokinetics of indocyanine green in the rabbit and rat.

The pharmacokinetic behavior of indocyanine green (ICG) in the rabbit can be described by a two-compartment open model, allowing for saturable transport of drug to the peripheral compartment and for its first-order elimination from the peripheral compartment. Use of this model led to the prediction of the accumulation of ICG in the plasma of a rabbit following the administration of repeated i.v. injections. Furthermore, studies conducted in the rat were also consistent with this model. One characteristic of the model is that above certain dose levels, the accumulation of ICG in the liver (i.e., the peripheral compartment) should reach a maximum independent of dose during certain time periods. This prediction was confirmed in a series of studies in the rat. The findings presented in this report provide evidence that a single model may be capable of explaining the variety of pharmacokinetic characteristics which have been reported for ICG, at least in the dose range studied.

Animals↗
PubMed1979

Noninvasive kinetic approach to the estimation of total hepatic blood flow and shunting in chronic liver disease--a hypothesis.

The intact hepatocyte theory of chronic liver disease suggests a relationship between the degree of shunting of total liver blood flow around the functional liver cell mass and the fraction of functional liver cell mass. By defining this relationship we have developed pharmacokinetic equations to permit the estimation of both total hepatic blood flow and the extent to which this blood flow is shunted. The method requires the determination of the systemic (hepatic) clearances of a high (e.g., indocyanine green [ICG]) and a low (e.g., antipyrine [AP]) extraction ratio drug in the same patient. Applying these equations to literature data obtained from patients with moderate or severe chronic liver disease and from patients with a surgical portacaval shunt, we find: (1) a modest decrease in total hepatic blood flow (16%) and a significant degree of shunting (27%) in patients with moderate chronic liver disease; (2) a substantially reduced total hepatic blood (52%) and extensive shunting (72%) in patients with severe chronic liver disease, and (3) a degree of shunting comparable to that estimated in patients with moderate chronic liver disease but a seriously compromised total hepatic blood flow (a reduction of 55% compared to normal) in patients with surgical portacaval shunts.

Antipyrine↗
PubMed1979

Screening methods using sulfamethazine for determining acetylator phenotype.

Analysis of sulfamethazine (SMZ) kinetics in man has revealed complexities including wide intersubject variability. In our study, an attempt was made to assess the potential influence of changes in nonmetabolic parameters (absorption and urinary elimination rate constants) on the markers of acetylation capacity normally used in clinical screening procedures to determine phenotype. Seven normal subjects were classified as slow (SA) or fast acetylators (FA) according to their metabolic rate constant for SMZ (Km), plasma SMZ half-life, and percentage of N-acetyl SMZ in a 6-hr blood sample (PI6), a 5- to 6-hr urine collection (UI5--6), or a 6-hr total urine collection (UI6). Computer simulations were applied to baseline SMZ kinetic data from these subjects, varying nonmetabolic kinetic parameters over experimentally defined ranges singly, or in parallel with 1 or more of the other parameters. The simulations indicate that all the usual phenotyping procedures were sensitive to changes in absorption and urinary elimination rate constants. While these predictions require experimental confirmation, results show that the PI6 method is least sensitive to such changes, suggesting this method may minimize errors in phenotyping screening.

Absorption↗
PubMed1979

Comparative pharmacokinetics of coumarin anticoagulants. XLII: Effect of phenobarbital on systemic availability of orally administered dicumarol in rats with ligated bile ducts.

The purpose of this investigation was to determine if the previously demonstrated inhibitory effect of phenobarbital treatment on the systemic availability of orally administered dicumarol in rats is related to the known effect of phenobarbital on bile output. It was found that phenobarbital had no apparent effect on the systemic availability of an aqueous dicumarol suspension in rats with ligated bile ducts. Compared to results obtained previously on normal rats, bile duct-ligated rats absorbed and eliminated dicumarol much more slowly and absorbed much less of the anticoagulant. On the other hand, the relative inductive effect of phenobarbital treatment on dicumarol elimination was similar in normal and in bile duct-ligated animals. The latter exhibited substantial serum transaminase elevations, indicative of liver damage presumably secondary to cholestasis. These results demonstrate that a drug-drug interaction can depend markedly on the pathophysiological status of the animals.

Animals↗
PubMed1979

Time course of carbamazepine self-induction.

Carbamazepine concentrations in plasma during repetitive oral dosing were analyzed by means of a nonlinear, variable parameter, regression program (VARPARM) assuming dose-to-dose changes in the apparent elimination rate constant of the drug. There was evidence of significant self-induction of carbamazepine metabolism as early as 1 or 2 days after initiation of the multiple-dose study. Additional self-induction appears to occur after about 2 weeks of treatment. The time course of carbamazepine self-induction appears to be complex, discontinuous, and prolonged.

Carbamazepine↗