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Biomedical subjects

M Gibaldi

Publications and source records attributed to M Gibaldi.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1975

Comparison of observed and predicted bioavailability of nortriptyline in humans following oral administration.

The first-pass equation based on the dose, hepatic blood flow, and total area under the plasma level-time curve after oral administration was used retrospectively to predict the bioavailability of nortriptyline after oral administration of 1 mg/kg-single oral doses to monozygotic and dizygotic twin pairs. The predicted values of bioavailability ranged from 45 to 85%, consistent with experimentally derived estimates of nortriptyline availability.

Administration, Oral↗
PubMed1975

Bioavailability of aspirin from commercial suppositories.

A comparison of the bioavailability of salicylate from five brands of commercially available aspirin rectal suppositories in an adult panel is presented. All brands show slow absorption compared to oral administration of the drug in tablet form. At best, about 40% of the dose (on the average) was absorbed when retention time in the bowel was limited to 2 hr. However, four out of the five brands give substantially lower absorption rates so that only about 20% of the aspirin is available.

Adult↗
PubMed1975

Time course and dose dependence of antacid effect on urine pH.

Daily administration of a proprietary magnesium and aluminum hydroxides suspension, 15 ml four times a day, to normal adult volunteers resulted in a statistically significant increase in urine pH on the 1st day of treatment. The urine pH's on the 2nd and subsequent days of treatment were statistically significantly higher than on the 1st day. A 7.5-ml dose of the antacid suspension, taken four times a day, had only a small and not statistically significant effect on urine pH, while 30 ml four times a day increased urine pH by approximately the same magnitude as the 15-ml doses. The effect of the antacid on urine pH persisted for at least 1 day after discontinuation of dosing.

Adult↗
PubMed1975

Predictability of blood levels of gentamicin in man.

Data from 42 patients were analyzed to determine the predictability of the peak serum level and the t1/2 of gentamicin on the bases of age, sex, body weight, serum concentration of creatinine, and blood hematocrit. Renal function was normal in 21 patients and impaired in 21. The most striking finding was the relatively poor predictability of t1/2 of gentamicin from serum concentration of creatinine. The overall correlation coefficient was 0.749 (P less than 0.001) in contrast to values of greater than 0.9 reported by others. tthere was a significant correlation of the t1/2 of gentamicin with the reciprocal of hematocrit (r * 0.647, P less than 0.001). Linear regression equations taking account of sex, serum creatinine concentration, and reciprocal of hematocrit provided a somewhat higher correlation coefficient (0.821) with the t1/2 of gentamicin than did the equation including serum creatinine concentration alone but were still not fully satisfactory. Thus the pharmacokinetics of gentamicin may not be adequately predictable from standardized equations or nomograms.

Adolescent↗