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Biomedical subjects

M Gibaldi

Publications and source records attributed to M Gibaldi.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1979

Accumulation kinetics of drugs with nonlinear plasma protein and tissue binding characteristics.

The purpose of this investigation was to study, by digital computer stimulation, the accumulation kinetics of drugs which exhibit concentration-dependent binding to tissues and either linear (constant free fraction) or concentration-dependent (increasing free action with increasing drug concentration) binding to plasma proteins. It was assumed that elimination rate is proportional to free drug concentration in plasma and that there occurs instantaneous equilibration of drug between vascular and nonvascular spaces. Nonlinear binding can yield, under certain conditions, apparently biexponential plasma concentration-time curves which may be misinterpreted as being representative of a linear and biexponential system. Such misinterpretation would cause the following errors in the prediction of drug accumulation and elimination kinetics during and after constant-rate infusion: (a) the time required to reach steady state may be overestimated, and (b) the prominence of the apparent distribution phase after cessation of infusion may be underestimated. Drugs with linear and nonlinear plasma protein binding characteristics differ with respect to the relaionship between infusion rate and steady-state concentration. This relationship is linear when plasma protein binding is linear. Steady-state concentration increases less than proportionally with increasing infusion rate if plasma protein binding is drug concentration dependent.

Blood Proteins↗
PubMed1979

Single point clearance estimation.

Linear relationships were observed between the log of total body clearance (C1B) and simulated serum concentrations (Cmin) six hours after a test dose of chloramphenicol, as well as between C1B and the reciprocal of Cmin. Correlation coefficients for these relationships were 0.988 and 0.977, respectively. Clearance estimates obtained from a single serum sample following a test dose of a drug may prove to be a useful method of predicting dosage requirements for individual patients.

Chloramphenicol↗
PubMed1978

Apparent volumes of distribution and drug binding to plasma proteins and tissues.

A pharmacokinetic model that incorporates linear binding of drug to plasma proteins and tissue indicates the same relationship between apparent volume of distribution and drug binding as that proposed by Gillette (1971) based on a simple distribution model. Apparent volume of distribution (V) is directly proportional to free fraction of drug in plasma (fp) and indirectly proportional to free fraction of drug in tissue (fT). In the case of a constant fT, a plot of V versus fp will be linear with an intercept equal to plasma volume (Vp). If fT changes with fp, an apparently linear plot may result but the intercept will exceed Vp. An approach to the calculation of fT, a composite binding parameter, is presented and illustrated by comparing the tissue binding of tolbutamide in patients during acute viral hepatitis and upon recovery.

Blood Proteins↗
PubMed1978

Interaction of chloramphenicol with phenytoin and phenobarbital. Case report.

The effect of chloramphenicol therapy (48 mg/kg/day) on the serum concentrations of phenytoin and phenobarbital was studied in a patient previously stabilized on anticonvulsant medications. Phenytoin, 12 mg/kg/day, and phenobarbital, 5 mg/kg/day resulted in serum concentrations averaging 10.8 microgram/ml before and 30.5 microgram/ml, after chloramphenicol therapy. A reduction in dose of both phenytoin and phenobarbital was required to minimize adverse effects during the course of chloramphenicol therapy. An average daily dose of phenytoin of 9.1 mg/kg resulted in an average serum concentration of 17.8 microgram/ml. A daily dose of phenobarbital of 4.0 mg/kg resulted in an average serum concentration of 37.1 microgram/ml. These changes indicate 50.5% and 40.4% decreases in clearance of phenytoin and phenobarbital. Multiple-dose nonlinear regression analysis of phenytoin and phenobarbital serum concentration data obtained during chloramphenicol therapy indicated a 62.5% and a 29.5% decrease in clearance. Subsequent serum concentration monitoring demonstrated a similar reduction in phenobarbital clearance when chloramphenicol was added to phenobarbital alone.

Adult↗
PubMed1978

Absorption kinetics of hydroflumethiazide.

The pharmacokinetics of hydroflumethiazide after oral administration of a 100-mg dose to 12 volunteers were evaluated to determine whether absorption of the drug is best described by zero-order or first-order absorption. Comparison of the two absorption models was based on three criteria: (1) correlation coefficients; (2) standard deviations of the parameter estimates; and (3) visual fits. Evaluation of the individual results in light of each criterion showed that the zero-order absorption model is the more appropriate one for describing the hydroflumethiazide data.

Administration, Oral↗
PubMed1978

Use of MULTDOS for pharmacokinetic analysis of ethosuximide data during repetitive administration of single or divided daily doses.

MULTDOS, a computer method to curve fit data obtained on multiple dosing, was used with either the 1969 or 1974 version of the NONLIN program to compare the pharmacokinetic parameters of ethosuximide during repetitive administration of single or divided daily doses. Elimination rate constants, excretion rate constants, and apparent volumes of distribution were similar between the two dosing regimens and essentially identical between the two nonlinear regression programs.

Computers↗
PubMed1977

Pharmacokinetic analysis of drug concentration data obtained during repetitive drug administration.

A digital computer curve-fitting method, designed to estimate pharmacokinetic model constants by utilizing all drug concentration-time data collected during repetitive dosing studies, was applied to data manifesting systematic dose-to-dose variability in one or another of the pharmacokinetic parameters. The method accurately determined dose-to-dose changes in absorption or elimination rate constants or in the apparent volume of distribution, and it would be useful for detecting phenomena such as self-induction and self-inhibition that may occur during multiple-dose administration. The method can also be used to analyze multiple-dose data of drugs exhibiting capacity-limited elimination and to obtain estimates of the Michaelis-Menten parameters.

Computers↗