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M Gibaldi

Publications and source records attributed to M Gibaldi.

At least 37 records · Page 2Linked to original sources
PubMed1987

Evaluation of in vivo drug release by numerical deconvolution using oral solution data as weighting function.

Determination of in vivo drug release using compartmental model analysis is hampered by problems such as flip-flop phenomena and vanishing exponential terms. The usefulness of numerical deconvolution to estimate in vivo drug release was evaluated in this study by means of simulated data comparing solid dosage forms with a solution as a reference standard. Concentration-time data were generated using the standard linear two-compartment body model with various first-order release and absorption rate constants. Random errors of 5 and 10% were added to data sets for further analysis. The results of the study using error-free data afforded excellent agreement with the theoretical values except in one case where the release rate constant was overestimated by 6%. When random error was added to the data, the resulting in vivo release profile showed considerable fluctuation and no single rate constant could be assigned. However, further analysis showed that the method does not create additional error during the calculating process, as previously suggested, but merely reflects the inherent error added to the raw data. If the raw data are poor, no useful information can be obtained without using an arbitrary technique such as smoothing or fitting. In this regard, the time course of drug release obtained after numerical deconvolution merits investigation.

Absorption↗
PubMed1987

The effect of sulfinpyrazone on the disposition of pseudoracemic phenprocoumon in humans.

The effect of sulfinpyrazone on the pharmacokinetics and disposition of the enantiomers of pseudoracemic phenprocoumon was assessed by analyzing serial plasma, urine, and fecal samples for parent drug and metabolites by GC/MS. Essentially all of the administered dose could be accounted for either as parent drug, known metabolites, or their conjugates. Phenprocoumon and the 7-hydroxymetabolite represented the major materials recovered. All drug-related materials excreted into the urine were extensively conjugated. Sulfinpyrazone treatment did not affect the hypoprothrombinemia produced by phenprocoumon nor did it significantly alter the plasma elimination kinetics of the individual (R)- and (S)-enantiomers. However, an apparent increased free fraction of both enantiomers in plasma and inhibition of 7-hydroxylation of (S)-phenprocoumon were observed in the presence of sulfinpyrazone. The results of this study are contrasted with those of a previous study on the interaction between sulfinpyrazone and the structurally similar coumarin anticoagulant warfarin.

4-Hydroxycoumarins↗
PubMed1987

The mechanism of the warfarin-rifampin drug interaction in humans.

The mechanism of the drug interaction in humans between warfarin and rifampin was investigated by monitoring the elimination kinetics and metabolic disposition of a single oral dose of pseudoracemic warfarin by GC/MS. The decrease in hypoprothrombinemia observed with concomitant administration of therapeutic doses of rifampin was accompanied by a substantial decrease in the elimination half-lives of both warfarin enantiomers. Rifampin increased the clearance of (R)-warfarin threefold and the clearance of (S)-warfarin twofold. The excretion profiles for warfarin and its metabolites in urine and feces were similar for both control and treated subjects with the exception that 4'-hydroxywarfarin (stereoselective for the (S)-enantiomer) was observed when rifampin was administered. 4'-Hydroxywarfarin is a metabolite of the drug hitherto undetected in vivo in humans. Based on formation clearance values estimated for 6-, 7-, and 8-hydroxywarfarin, rifampin appears to increase the clearance of the parent drug by induction of the cytochrome P-450 isozyme(s) responsible for aromatic hydroxylation.

Adult↗
PubMed1986

The warfarin-sulfinpyrazone interaction: stereochemical considerations.

To allow the simultaneous evaluation of the interaction between sulfinpyrazone and each enantiomer of racemic warfarin, pseudoracemic warfarin (1:1 12C-R(+) and 13C-S(-)warfarin) was given to six normal subjects both before and during oral sulfinpyrazone dosing. Serial blood and urine samples were analyzed for unchanged warfarin and its metabolic products by GC/MS. A mass balance of an oral dose of pseudoracemic warfarin, containing a tracer quantity of 14C-warfarin, was carried out in one of the subjects by monitoring 14C levels in urine and feces for 15 days. Concomitant sulfinpyrazone dosing markedly increased hypoprothrombinemia, decreased clearance of (S)-warfarin, and increased clearance of (R)-warfarin. Sulfinpyrazone also decreased the urinary excretion of warfarin-related products but increased their fecal excretion by an equivalent amount. Virtually all of the administered warfarin dose could be accounted for either as unchanged drug or known metabolites. Pharmacokinetic analysis of the data suggests the following: At least four distinct enzymes (two oxidases and two reductases) are involved in the metabolism of warfarin. Sulfinpyrazone increases the hypoprothrombinemia caused by warfarin primarily by inhibition of the cytochrome P-450-mediated oxidation of (S)-warfarin, the biologically more potent enantiomer. The increased clearance of (R)-warfarin results not from induction, but from its selective displacement from plasma protein binding sites.

Administration, Oral↗
PubMed1985

Assessment of drug absorption after oral administration.

Simulated data using a linear two-compartment body model (2CBM) with drugs having different absorption characteristics and dosage forms with different dissolution rates were used to evaluate the inherent problems of pharmacokinetic data analysis (flip-flop phenomenon and vanishing exponential terms). When absorption from solution is slow or release from the solid dosage form is rate limiting, the characteristic nose of the 2CBM was lost and a one-compartment model prevailed. After the 2CBM disposition kinetic parameters were obtained from solution data, absorption kinetics were evaluated by the Loo-Riegelman method. The data were also evaluated by the statistical moments method. The statistical moments method consistently demonstrated superiority in regard to providing reliable results and ease in calculation. The information provided can be particularly useful for in vivo-in vitro correlation.

Administration, Oral↗
PubMed1984

Evaluating drug absorption after oral administration. Some problems and some solutions.

Quantitative assessment of drug absorption remains a difficult task, because the multiple-compartment disposition of a drug may not be obvious after oral administration (the problem of the vanishing exponential) and the macroconstants are indistinguishable. For these reasons, proper analysis of the drug absorption based on the apparent behavior of oral data without intravenous reference curve rarely provides absorption information useful for in vivo - in vitro correlations. When intravenous reference curve is available, compartment model used for analysis of the oral data should be corresponding to the iv data such as the Loo - Riegelman method. The model independent statistical moments method is one of the preferable alternatives because of its ease of computation and its potentially smaller error, if absorption can be assumed to be first-order.

Administration, Oral↗
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↗