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At least 19 recordsLinked to original sources
PubMed1979

Using pharmacokinetics in drug therapy. IV: Consideration in applying pharmacokinetic and pharmacodynamic estimates to antihypertensive dosage regimens.

A theory explaining the pharmacokinetics of drugs with direct and rapidly reversible pharmacologic effects is reviewed, and the application of this theory to individualizing dosage regimens for antihypertensive drugs is discussed. In a few studies, investigators have correlated, under controlled conditions and in a small number of patients, the pharmacokinetic variables needed to individualize minoxidil and clonidine dosage regimens with clinical responses (mean arterial blood pressure). The potential clinical application of these correlations to other antihypertensive drugs was studied by retrospectively analyzing diastolic and mean arterial blood pressure data reported in 26 published studies of seven antihypertensive drugs. The wide interpatient variation recorded in the dose-response plots derived from the published data yielded pharmacodynamic values of little reliability or predictive value in individualizing antihypertensive dosage regimens. Use of retrospective data analysis for obtaining the necessary pharmacokinetic values to individualize antihypertensive dosage regimens is discouraged.

Antihypertensive Agents↗
PubMedDate not supplied

Pharmacodynamics and pharmacokinetics of psycholeptic drugs in the course of radiation disease. The effect of premedication with cystamine on pharmacodynamics and Pharmacokinetics of nitrazepam.

Pharmacodynamics and pharmacokinetics of psycholeptic drugs in the course of radiation disease (I). Effect of premedication with cystamine on pharmacodynamics and pharmacokinetics of nitrazepam. Acta Physiol. Pol. 1977, 28 (2): 161--168. In the experiments carried out on rats the radiation disease was evoked by exposure to 600 R. The strongest radioprotective action of cystamine was found on the 3-rd day of radiation disease. The tendency to normalization of both the pharmacodynamics (exploring mobility and anticonvulsant action) and pharmacokinetics of nitrazepam in the animals premedicated with cystamine was described.

Animals↗
PubMed2026

Effect of Food on Balcinrenone/Dapagliflozin Pharmacokinetics and the Pharmacokinetics of Balcinrenone When Dosed with a P-gp Inhibitor.

Balcinrenone (AZD9977) is a novel selective non-steroidal mineralocorticoid receptor antagonist with a distinct mode of action being developed as a fixed-dose combination with the sodium-glucose cotransporter-2 inhibitor dapagliflozin for the treatment of heart failure with impaired kidney function, and chronic kidney disease. In this Phase 1 randomized open-label three-way crossover study we investigated the effect of food on balcinrenone/dapagliflozin pharmacokinetics, and the pharmacokinetics of balcinrenone when dosed with a P-glycoprotein (P-gp) inhibitor. Fourteen healthy participants were administered an oral capsule of balcinrenone/dapagliflozin 40 mg/10 mg in three dosing periods: fasted (reference), fed (high-fat, high-calorie meal) and with a P-gp inhibitor (quinidine 300 mg &#xd7; 2). Balcinrenone exposure was comparable in the fed and fasted states (geometric mean ratios [GMRs] [90% CI]: maximum plasma concentration [Cmax] 1.05 [0.88, 1.25]; area under the plasma concentration-time curve from time 0 to infinity [AUCinf] 1.12 [1.06, 1.19]). In the fed state, dapagliflozin AUCinf was comparable to the fasted state (GMR [90% CI] 1.05 [1.01, 1.09]), whereas Cmax was decreased (GMR [90% CI] 0.59 [0.51, 0.69]), in line with previous dapagliflozin food interaction studies. Co-administration with quinidine increased balcinrenone exposure: GMRs (90% CI) 1.48 (1.24, 1.76) and 1.24 (1.17, 1.31) for Cmax and AUCinf, respectively, but AUC fold increase was <2, the level used for classification of sensitive P-gp substrates. All interventions were well tolerated. In conclusion, this study supports dosing of balcinrenone/dapagliflozin without regard to food. Balcinrenone is not considered a sensitive P-gp substrate. No P-gp based dosing precautions are warranted based on this study.

Adult↗
PubMed1975

Comparative pharmacokinetics of coumarin anticoagulants XV: relationship between pharmacokinetics of dicumarol and warfarin in rats.

The distribution, elimination, and anticoagulant effect of dicumarol and warfarin were determined in adult males rats following intravenous injection of single doses of these drugs in crossover experiments. The biological half-life of dicumarol ranged from 5 to 28 hr; that of warfarin ranged from 9 to 30 hr. There was a statistically significant correlation between the following pharmacokinetic characteristics of dicumarol and warfarin in individual animals: biological half-life, apparent volume of distribution, total plasma clearance, and concentration in plasma eliciting one-half the maximum anticoagulant effect (effective concentration). The mean ratio of the respective biological half-lives (warfarin/dicumarol) was 1.42, and that of the apparent volumes of distribution was 1.50. The ratio of the effective plasma concentrations (dicumarol/warfarin) was correlated negatively with the half-life of dicumarol and positively with the ratio of the half-life values (warfarin/dicumarol) in individual animals. Additional studies with serum samples from other rats showed pronounced interindividual differences in the serum protein binding of both dicumarol and warfarin and a strong correlation between the protein binding of these two drugs in serum of individual animals. The results of this study, together with the results of previous studies in this series, indicate that serum protein binding is the major determinant of interindividual differences in the pharmacokinetics of dicumarol and warfarin in rats under these experimental conditions.

Animals↗
PubMed1979

Pharmacokinetics of morphine and its surrogates. III: Morphine and morphine 3-monoglucuronide pharmacokinetics in the dog as a function of dose.

The pharmacokinetics of morphine and its derived metabolite, morphine 3-monoglucuronide, were studied in normal and bile-cannulated dogs. High doses (7.2-7.7 mg/kg iv) caused renal and biliary shutdowns and time lags in urinary drug and metabolite excretion and in biliary secretion of the hepatically formed conjugate. Intermediate doses (0.41-0.47 mg/kg iv) inhibited urine flow but not renal clearance. Low doses (0.019-0.07 mg/kg iv) had no apparent effect. Dose-related effects on the total, metabolic, and biliary clearances imply saturable enzymes and/or dose-inhibited hepatic flows, accounting for the major elimination half-lives of 83 +/- 8 and 37 +/- 13 min at the high and low doses, respectively. The slow terminal phase in plasma morphine and metabolite elimination and urinary accumulation is due apparently to the enterohepatic metabolite recirculation after biliary excretion, gastrointestinal hydrolysis, and hepatic first-pass reconjugation. Bile-cannulated dogs showed no fecal drug and no slow terminal plasma and urine elimination phases. Intravenous morphine 3-monoglucuronide was eliminated only renally and showed neither biliary excretion nor prolonged hepatically formed glucuronide elimination. Hepatic morphine clearances at normal therapeutic doses parallel hepatic blood flow and explain the lack of oral morphine bioavailability by anticipating complete first-pass liver metabolism. Renal morphine and morphine conjugate clearances were 85 (+/- 9 SEM) and 41 (+/- 4 SEM) ml/min, respectively, indicating glomerular filtration for the latter and glomerular filtration plus tubular secretion for the former. Urinary morphine and morphine conjugate excretion accounted for approximately to 83% of the dose. Biliary secretion accounted for 11-14% of the dose. Morphine showed dose-independent plasma protein binding of 36 (+/- 1 SEM) % and a red cell-plasma water partition coefficient of 1.11 +/- 0.04 SD. New equations were developed to model the discontinuous morphine and morphine metabolite pharmacokinetics.

Animals↗
PubMed1978

Using pharmacokinetics in drug therapy II: Rapid estimates of dosage regimens and blood levels without knowledge of pharmacokinetic variables.

A modification of the superposition method, which yields fast and reasonably accurate estimates of dosage regimens and steady-state maximum and minimum blood levels, is described. In the modified superposition method, input data are obtained from the blood, plasma or serum concentration vs time profile resulting from administration of a single dose of the drug. These estimates are valid only when the pharmacokinetics of the drugs are linear and elimination from the body occurs according to first-order kinetics. Limitations of the method are discussed. It is concluded that this is a rapid and clinically useful method for pharmacokinetic estimations.

Drug Administration Schedule↗
PubMed1975

Hydrodynamic analog model for pharmacokinetics II: critical examination of model and its contribution to pharmacokinetics.

A comparison of the conventional pharmacokinetic models and the previously proposed hydrodynamic diffusion analog model is presented. A significant result that an n-compartment system can exhibit at best (n - 1) extremum times in the concentration-time plot of the central compartment under appropriate values of physiological parameters is presented. The observation of kinks experimentally in certain physiological-drug systems is thus shown to be amenable to explanation.

Dicumarol↗
PubMed1978

Comparative pharmacokinetics of coumarin anticoagulants XXXV: Examination of possible pharmacokinetic interaction between (R)-(+)- and (S)-(--)-warfarin in humans.

The elimination kinetics and anticoagulant effect produced by single 1.5-mg/kg doses of (R)-(+(-, (S)-(--)-, and racemic warfarin were determined in 10 healthy men. The results obtained in experiments with the individual enantiomers were used to predict the elimination kinetics and anticoagulant effect of racemic warfarin, assuming that there is no interaction between the two enantiomers. These predictions were compared to experimental results, and no significant differences were observed. This finding suggests that there are no pronounced pharmacokinetic or pharmacodynamic interactions between single large doses of (R)-(+)- and (S)-(--)-warfarin in humans.

Adult↗
PubMed1978

Pharmacokinetics of morphine and its surrogates I: comparisons of sensitive assays of morphine in biological fluids and application to morphine pharmacokinetics in the dog.

A sensitive isotope derivatization assay was developed to quantify morphine in biological fluids in the nanogram per milliliter range. Morphine, derivatized with 3H-dansyl chloride, was separated from the reaction products by TLC. The spots were scraped from the plate, and the eluted radioactivity was determined by liquid scintillation. The standard deviations of this morphine assay were +/- 18.6 ng/ml in 100 microliter of plasma and +/- 1.86 ng/ml in 1 ml of plasma. The GLC analysis of pentafluoropropionated morphine in the range of 0--5 ng of morphine/ml of plasma had a standard deviation of +/- 0.46 ng/ml when 1 ml of plasma was taken. Liquid scintillation spectrometric analysis of 14C-morphine had a sensitivity of 1.5 ng/ml of plasma at double the background. There were no significant differences among the liquid scintillation, electron-capture GLC, and radioisotpoe derivatization methods for morphine obtained from the plasma of a dog given 14.00 mg iv of morphine. Morphine conjugates were assayed as morphine after the acid hydrolysis of plasma and urine preextracted to remove unconjugated morphine, and the equivalence of various methods was demonstrated to monitor plasma and urine pharmacokinetics in a dog.

Animals↗
PubMed1978

Pharmacokinetics and metabolite-pattern of 8-methoxypsoralen in man following oral administration as compared to the pharmacokinetics in rat and dog.

Following oral administration of 14C labelled 8-methoxypsoralen (8-MOP) in man the plasma level course, the metabolite-patterns and the elimination of the parent compound and its metabolites have been investigated. Additionally the results discovered have been compared with the data of pharmacokinetics on dog and rat. In man and rat the plasma protein binding of 8-MOP has been determined. Maximal levels of the total radioactivity in the plasma were achieved 2 h after dosing. At this time 8-MOP represents 50% of the radioactivity in the plasma. The plasma protein binding in vitro of 14C 8-MOP valued from 88% to 91% in man, and between 75% and 83% in the rat. Urinary elimination of the total radioactivity as a measure of the extent of absorption varies greatly and depends on the therapeutic formulation being employed. Following the administration of the solution 74% is recovered within 48 h. Faecal elimination of the total radioactivity reached 14% within 3 days. The metabolite-pattern does not show the unchanged 14C 8-MOP. Several polar metabolites occur in the urine among which biochemical conjugates have been recognized. Only polar metabolites are observable in the faeces from which the radioactivity is incompletely extractable. From a comparison of the metabolite profiles, the rat as well as the dog seem to be a useful animal species for experimental investigations with 8-MOP.

Administration, Oral↗
PubMed1975

Pharmacokinetic analysis of ampicillin concentration in neonates: comparison of two pharmacokinetic models and of two numerical methods.

Ampicillin blood levels after i.m. injection were analysed according to a one and a two-compartment pharmacokinetic model. The two-compartment model gave no substantially better fit to the data than a one-compartment model. To fit the one-compartment model two computer programs based on different numerical methods, were tested. The BMD program gave satisfactory results in all cases.

Ampicillin↗
PubMedDate not supplied

Pharmacokinetic interaction of psychotropic drugs. I. Divergent effect of mianserin on pharmacokinetics and pharmacodynamics of amphetamine.

Pharmacokinetics of amphetamine and stereotypy caused by this drug was studied after premedication with two doses of mianserin (2 and 10 mg/kg). High doses of mianserin depressed the amphetamine level in blood and cerebral tissue and increased the stereotypy. The results suggest that the potentiation of the action of amphetamine by mianserin is mainly due to pharmacodynamic synergism and depends on the blockade of central serotonergic receptors by mianserin.

Amphetamine↗