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M Gibaldi

Publications and source records attributed to M Gibaldi.

At least 55 records · Page 3Linked to original sources
PubMed1977

Physiologically based pharmacokinetic model for digoxin distribution and elimination in the rat.

A plasma flow rate-limited pharmacokinetic model was developed to describe the distribution of digoxin to the heart, liver, kidneys, skeletal muscle, and GI tract in the rat. The model also provides for renal, hepatic (metabolic and biliary), and GI clearance as well as for biliary and GI secretion and GI reabsorption of digoxin. Predicted concentrations of digoxin in the heart, liver, skeletal muscle, and plasma were consistent with experimental observations in conscious rats after an intravenous dose. The model was extended to describe digoxin concentrations in the plasma of bile duct-ligated rats and ureter-ligated rats, simply by modifying appropriate clearance parameters. Excellent agreement was obtained between predicted and observed urinary excretion rates of digoxin for 12 hr after in intravenous dose to normal and bile duct-ligated rats.

Animals↗
PubMed1977

Biopharmaceutic factors that influence effects of anticholinergic drugs: comparison of propantheline, hexocyclium, and isopropamide.

The antisecretory (determined from salivary flow rates) and antimotility (determined from riboflavin absorption) effects of usually recommended doses of propantheline, hexocyclium, and isopropamide were compared in four adult volunteers. Both propantheline and hexocyclium significantly decreased salivary flow and increased riboflavin absorption. Although the usual dose of propantheline was about twice as effective as the usual dose of hexocyclium in suppressing salivary flow, these doses produced comparable effects on riboflavin absorption. Isopropamide had little or no effect on either the salivary flow rate or riboflavin absorption. Propantheline and hexocyclium elicited little effect on salivary flow when administered after a meal. Prolonged-release dosage forms of these drugs produced effects comparable to those produced by much smaller doses in conventional tablets and gave no indication of providing prolonged anticholinergic effects.

Adult↗
PubMed1977

Effect of coadministered salicylamide on terbutaline metabolism in rats.

Concomitant oral administration of salicylamide (200 mg/kg) and 3H-terbutaline (1 mg/kg) to rats with ligated bile ducts decreased absorption of terbutaline from the gut from 73 to 56% as measured by urinary excretion of radioactivity in 48 hr. No increase in the fraction of terbutaline excreted unchanged was observed, suggesting that salicylamide does not substantially inhibit the conjugation of terbutaline with glucuronic acid. An increase in the fraction of terbutaline excreted unchanged observed in normal animals may result from enhanced excretion of terbutaline glucuronide into bile rather than from inhibition of conjugation.

Animals↗
PubMed1977

Physiologically based pharmacokinetic model for digoxin disposition in dogs and its preliminary application to humans.

A physiologically based pharmacokinetic model for digoxin disposition developed in the rat was modified to account for the interspecies differences in tissue-to-plasma digoxin concentration ratios and applied to the dog. The model provided a quantitative assessment of the time course of digoxin concentrations in dog plasma, various tissues, and urine. It also predicted the effect of renal failure on digoxin pharmacokinetics in the dog. An attempt to scale the dog model to humans by simply considering differences in organ volumes, organ flow rates, and digoxin clearances was partially successful. Good predictions of plasma digoxin concentration and urinary digoxin excretion after a single dose and of steady-state plasma, heart, and skeletal muscle digoxin concentrations were obtained. However, the model predicted considerably higher kidney digoxin concentrations than are actually found. Although the model adequately characterized the time course of digoxin concentrations in patients with moderate renal impairment, it provided a relatively poor fit to that observed in anuric patients.

Animals↗
PubMed1977

Drug distribution in renal failure.

Plasma protein binding of many drugs is impaired in patients with renal disease. This often results in a larger apparent volume of distribution and a larger clearance of the drug compared to that observed in patients with normal renal function. Hence, renal disease can also influence the pharmacokinetics of drugs that are eliminated from the body by biotransformation rather than by renal excretion, Repetitive administration of a given dose of a drug that is eliminated from the body by nonrenal mechanisms may result in considerably lower steady-state concentrations of total drug in the plasma of patients with renal disease than in that of patients with normal renal function. On the other hand, in the absence of liver disease, the average steady-state serum concentration of free (unbound) drug is likely to be the same in both groups of patients. For this reason, it is probably not necessary to change the usual daily dose of a drug that is eliminated from the body by nonrenal mechanisms when it is given to a patient with renal disease. However, such drugs should be administered in divided doses to minimize adverse effects.

Antipyrine↗
PubMed1977

Pharmacokinetics of erythromycin on repetitive dosing.

Serum erythromycin concentration data from several repetitive dosing studies were analyzed with newly developed computer methods for fitting multiple-dose data and generating nonlinear least-squares estimates of pharmacokinetic parameters. This analysis indicates that the pharmacokinetics of erythromycin can be described by a one-compartment linear model with the following characteristics: (a) a lag time between the time of drug administration and the onset of absorption; (b) apparent zero-order rather than first-order absorption; (c) dose-to-dose variability in the rate and extent of absorption; and (d) day-to-day variability in the kinetics of elimination. The bioavailability of the third dose of erythromycin on a given day is considerably lower than that of the second dose or of the fourth and last dose of the day. The average apparent half-life of erythromycin was 1.8 hour on day 1 and 2.6 hours on day 3 of the repetitive dosing regimen.

Adult↗
PubMed1977

Plasma protein binding and metabolic clearance of phenytoin in the rat.

The purpose [corrected] of this investigation was to determine the effects of certain changes in plasma protein binding on the disposition of phenytoin after i.v. administration in the rat. Treatment of rats with sulfisoxazole and oleic acid significantly reduced plasma protein binding of phenytoin. The displacement of phenytoin from plasma proteins by sulfisoxazole had no significant effect on the elimination of phenytoin whereas comparable displacement by oleic acid produced an increase in the apparent volume of distribution and a marked decrease in the metabolic clearance of the drug. A similar difference in metabolic clearance was noted when phenytoin elimination was determined as a function of the intrinsic ability of the rat to bind phenytoin in the plasma. Rats showing relatively high plasma protein binding of phenytoin cleared the drug much more rapidly than rats showing relatively low plasma protein binding of phenytoin. Assuming that an endogenous inhibitor is responsible for both the decreased plasma protein binding and decreased metabllic clearance of phenytoin in rats with an intrinsically reduced ability to bind phenytoin in plasma, this inhibitor is evidently similar to oleic acid in its effects.

Animals↗
PubMed1976

Pharmacokinetics in clinical practice. 2. Applications.

The pharmacokinetic concepts introduced and defined in a preceding article are now applied to the management of drug therapy for the individual patient. The factors that affect the time course of drug concentrations in plasma produced by repetitive administration include the dosing rate, total clearance, biologic half-life, and systemic availability of the drug. A clinical pharmacokinetics service can monitor drug concentrations in biologic fluids, design individualized drug-dosing regimens, and carry out pharmacokinetic diagnostic work-ups to help determine the reasons for a patient's unusual response to drug therapy.

Administration, Oral↗
PubMed1976

Pharmacokinetics in clinical practice. I. Concepts.

Important concepts of pharmacokinetics, such as the biologic half-life, clearance, and bioavailability of drugs, can be utilized to describe and predict the time course of drug concentrations in plasma as a function of dose and frequency of drug administration. In quantitative terms, they can serve to characterize the individuality of the patient, including the effects of disease, with respect to drug absorption, distribution, excretion, and metabolism.

Administration, Oral↗
PubMed1976

Time-dependent change in renal clearance of bethanidine in humans.

Blood levels and urinary excretion rates of bethanidine were determined in three normal human subjects following oral administration of a single dose of the drug. The postabsorptive decline of blood concentration with time was noticeably slower than the corresponding decline in the urinary excretion rate. The discrepancy can be attributed to a continual decrease in the renal clearance of bethanidine throughout the study. Therefore, pharmacokinetic modeling of urinary excretion data alone would lead to erroneous conclusions concerning the persistence of drug in the blood.

Bethanidine↗
PubMed1976

Influence of cholestasis on drug elimination: pharmacokinetics.

A two-compartment model representing the body and the GI tract, with elimination occurring in each compartment, was used to study, in theory, the influence of impaired biliary excretion on drug disposition. The results suggest that cholestasis can either increase or decrease a drug's half-life, depending upon the relative values of the two elimination rate constants, In all cases, however, impaired biliary excretion reduced the initial elimination of drug from the body and increased the half-life of the alpha-phase of drug disposition.

Biopharmaceutics↗
PubMed1975

Pharmacokinetics of bethanidine in hypertensive patients.

The pharmacolinetics of bethanidine-14C was studied in three hypertensive patients. A 25-MG DOSE OF BETHANIDINE-14 C hemisulfate was administered intravenously. Plasma levels of drug were measured over the first 6 hr. In 3 to 4 days, 89% to 94% of the dose was excreted in the urine. Thin-layer chromatography (TLC) and isotope dilution analysis of the urine samples indicated that only intact bethanidine was excreted. Plasma level and urinary excretion rate profiles had miltiphasic characteristics. Estimated half-lives of the terminal phase ranged from 7 to 11 hr. Average renal clearance over the initial 6 hr approached renal plasma flow. In 2 of the patients, renal clearance between 2 and 4 hr after administration was reduced to one-helf that observed during the initial 2-hr period. After single oral administration of a 25-mg dose of bethanidine-14C hemisulfate, 48% of 61% was excreted in urine and 15% to 48% in feces. Peak urinary excretion rates were reached 6 hr following administration. The urinary excretion kinetics of bethanidine during and after repetive oral dosing was also studied. A 25-mg dose was dividied into 12 to 16 equal doses and administered avery 6 hr. A larger fraction of the cumulative dose was recovered in the urine (72% to 74%) than after the single dose, suggesting higher availability at the lower dose. Steady-state urinary excretion rates were achieved in 4 to 7 doses. The steady-state urinary excretion levels were consistent with pharmacolinetic predictions based on single oral dose data. When 2 of the patients were given imipramine for 2 days prior to an oral 25-mg dose of bethanidine-14C hemisulfate, the terminal half-lives of the urinary excretion rate profiles were shorter than those in the same patients not given imipramine.

Administration, Oral↗
PubMed1975

Pharmacodynamics of minoxidil as a guide for individualizing dosage regimens in hypertension.

The antihypertensive effect of minoxidil was studied in 6 patients with varying degrees of hypertension. Their baseline mean arterial pressure (MAP bi) ranged from 122 to 197 mm Hg. Single oral doses between 2.5 and 25 mg were administered in sequence and the time-course of hypotensive action was followed. We have reported previously that when the peak lowering of MAP is linearly regressed against log dose, both the dose-response slope (M) and threshold dose (Dt) are positively correlated with the MAP bi of individual patients. This investigation focuses on the temporal pattern of effect. It was found that the hypotensive effect of minoxidil declined linearly with time at a rate consistent with an average effective biologic half-life of about one day. The rate of decline of effect was apparently independent of dose but was dependent on MAP bi. Since both response to and duration of effect of minoxidil are functions of MAP bi, there is an abvious need to individualize dosage regimens based on the severity of disease. Using pharmacodynamic parameters, guidelines for loading dose, maintenance dose, and dosing frequency as a function of the degree of hypertension are suggested. Loading dose requirements were found to increase with MAP bi while maintenance doses were largely independent of the severity of the disease. Frequently of dosing was found to range from 3 times a day in very severe hypertension to once a day in moderate hypertension.

Administration, Oral↗
PubMed1975

Biopharmaceutic influences on the anticholinergic effects of propantheline.

With reduction of salivary flow rates as an index of anticholinergic response, 3 subjects manifested demonstrable effects shortly after ingestion of 15-mg doses of propantheline in conventional tablets. Ingestion of this dose i-mediately after a standardized breakfast substantially reduced the anticholinergic effects. In 1 subject, a dose-response relationship was noted after 15 mg and 30 mg doses under both fasting and fed conditions, but at each dose level the influence of food was clear. Administration of a 30-mg dose of propantheline in a commercially available "prolonged-acting" tablet induced little if any anticholinergic effects; in 2 subjects, marginal but fleeting indications of salivary suppression were noted about 4 hr after ingestion, while no effects were observed in the third subject (even after 2 "prolonged-acting" tablets).

Adult↗