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Biomedical subjects

E R Garrett

Publications and source records attributed to E R Garrett.

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

Separation and analysis of delta 9-tetrahydrocannabinol in biological fluids by high-pressure liquid chromatography and GLC.

High-pressure liquid chromatographic (HPLC) systems were developed to separate quantitatively delta 9-tetrahydrocannabinol from heptane-extractable lipoidal and other endogenous substances in biological fluids. These substances interfered with the quantitation by flame-ionization GLC of the unmodified compound and by electron-capture GLC of the pentafluorobenzoyl derivative. Reversed-phase HPLC elution, with 47% acetonitrile in water, and normal-phase HPLC with 25% chloroform in heptane separated delta 9-tetrahydrocannabinol from 11-hydroxy-delta 9-tetrahydrocannabinol and other monohydroxylated tetrahydrocannabinols. These systems also purified stock solutions of delta 9-tetrahydrocannabinol from accompanying contaminants. The various monohydroxylated tetrahydrocannabinols were resolved from each other in the normal phase, 80% chloroform in heptane. The delta 8- and delta 9-tetrahydrocannabinols were separable in the normal phase with 5% tetrahydrofuran in hexane. The GLC analysis of pentafluorobenzoylated delta 9-tetrahydrocannabinol had a sensitivity of 1 ng/ml of plasma, with an estimated 5% standard error with the developed extraction and GLC procedures. Radiochemical analysis of the HPLC-separated fraction had a sensitivity of 0.2 ng/ml of plasma, with an estimated 2% standard error. There was no significant difference between the liquid scintillation and electron-capture GLC assays of the HPLC-separated delta 9-tetrahydrocannabinol obtained from the plasma of dogs administered the drug. Radiolabeled compounds can be added to plasma samples as internal standards to determine the recovery efficiencies of the several procedures in the analysis of unlabeled tetrahydrocannabinol.

Animals↗
PubMed1977

Pharmacokinetics of beta-methyldigoxin in healthy humans I: intravenous studies.

The pharmacokinetics of intravenously administered solutions of 0.30-and 0.60-mg bolus doses of 3H-beta-methyldigoxin, labeled in the 12alpha-position, were dose independent. Individual radioactivities assignable to the parent drug and specifically identified metabolites after TLC separation were followed in the plasma, urine, and feces. A sum of four exponentials described the plasma beta-methyldigoxin data with apparent half-lives of 0.04, 0.33, 3.5, and 41 hr. beta-Methyldigoxin was 10% plasma protein bound and had a red blood cell-plasma water partition coefficient of 0.9. The only significant metabolite observed in plasma was digoxin, although glucuronides and sulfates of beta-methyldigoxin, digoxin and digoxigenin also were observed in urine. As much as 92 +/- 3% of the dose was excreted by all processes by 144 hr. Of this amount, renal excretion accounted for fractions that were 0.47 unchanged, 0.35 digoxin, and 0.058 water-soluble metabolites. The fraction in the feces was 0.13. The urine flow independent renal clearances of beta-methyldigoxin and derived digoxin were 59 and 206 ml/min, respectively. The metabolism was a relatively fast process. The terminal pseudo-steady-state elimination of beta-methyldigoxin with a half-life of 41 hr was reached 27 hr after drug administration and was primarily dependent on the slow release of sequestered or distributed drug drom the tissues into the central compartment. The drug and metabolite levels in plasma and urine were consistent with analog computer fitting to the proposed pharmacokinetic multicompartmental model.

Adult↗
PubMed1977

Pharmacokinetics of beta-methyldigoxin in healthy humans II: Oral studies and bioavailability.

The pharmacokinetics of orally administered aqueous 3H-beta-methyldigoxin solutions were studied at two dose levels, 0.3 and 0.6 mg, in healthy human subjects. The drug and its metabolites were specifically assayed in biological fluids and compared with results after intravenous doses to the same subjects. No significant dose dependency was observed. The apparent half-life of absorption was 16+/-6 min (SEM). Digoxin was the only metabolite observed in the plasma and comprised 28.6+/-3.7% of the dose in the urine. 3H-beta-Methyldigoxin, renally excreted unchanged, comprised 25.7+/-1.7% (SEM). Water-soluble metabolites in the urine comprised 9.0+/-1.8%. Fecal and urinary excretion accounted for 85% of the dose at 144 hr. The oral absorption of unchanged 3H-beta-methyldigoxin from solution was 59+/-6% by area under the curve methods and 60+/-4% by renal excretion. A total of 73% of the dose in the solution was absorbed as beta-methyldigoxin and digoxin. First-pass metabolism prior to absorption was largely prehepatic and assignable to GI degradation; 21.9+/-2.8% was degraded with 12.8+/-4.0% to digoxin and 9.1+/-4.0% to water-soluble metabolites. From 14 to 18% of the administered oral dose did not reach the systemic circulation. Analog computer fitting of plasma and urine levels of drug and digoxin was consistent with the first-pass premise with a delayed absorption of GI-generated digoxin and other metabolites. There were no significant differences between the oral absorption of a tablet formulation and the solution. Orally administered beta-methyldigoxin solution delivered 97% cardioactivity as itself and digoxin with respect to an equivalent amount of intravenously administered digoxin. This value contrasts to the 140% delivered by intravenously administered beta-methyldigoxin on the premise of pharmacodynamic equivalence of systemically appearing digoxin and beta-methyl-digoxin. Literature reports on the oral bioavailability of solutions and solid dosage forms of digoxin were critically reviewed, but no reliable comparison of the extent and reproducibility of oral absorption of cardioactive agents from administered digoxin or beta-methyldigoxin could be made from the widely variable digoxin studies with nonspecific assays.

Administration, Oral↗
PubMed1977

Pharmacokinetics of beta-methyldigoxin in healthy humans III: Pharmacodynamic correlations.

Significant decreases in left ventricular ejection time and heart rate were observed after the oral and intravenous administration of beta-methyldigoxin. The time course of this action correlated with the time course of beta-methyldigoxin and its active metabolite, digoxin, in their deepest pharmacokinetic compartments and not with their plasma levels. This pharmacodynamic activity peaked (decrease of 6.3% at 0.6 mg iv and 3.5% at 0.3 mg iv; decrease of 3.8% at 0.6 mg po and 4.5% at 0.3 mg po) at about 10 hr, concomitantly with the amounts of beta-methyldigoxin in its deepest compartment and showed a terminal half-life equivalent to the 41 hr for beta-methyldigoxin. The relative peak heights and area under the ejection time-time curves indicated a linear dose-response relationship on intravenous administration and an effect greater than that reported for larger amounts of digoxin. The time course of heart rate action correlated (8.3 and 12.5% decreases with 0.3 and 0.6 mg iv, respectively; 6.5 and 9.5% decreases with 0.3 and 0.6 mg po, respectively) with the time course of beta-methyldigoxin and its metabolite digoxin in shallower pharmacokinetic compartments (peaks at approximately 80 min intravenously and 135 min orally), and significant effects had disappeared by 10 hr after drug administration. This finding indicated that the biophases differ for ejection time and heart rate action. Mean arterial blood pressure could not be correlated with the time course of drug, although a small consistent decrease (4-8%) was observed from 22 to 72 hr after drug administration.

Digoxin↗
PubMed1977

Pharmacokinetics of delta9-tetrahydrocannabinol in dogs.

The pharmacokinetics of intravenously administered 14C-delta9-tetrahydrocannabinol and derived radiolabeled metabolites were studied in three dogs at two doses each at 0.1 or 0.5 and 2.0 mg/kg. Two dogs were biliary cannulated; total bile was collected in one and sampled in the other. The time course for the fraction of the dose per milliliter of plasma was best fit by a sum of five exponentials, and there was no dose dependency. No drug was excreted unchanged. The mean apparent volume of distribution of the central compartment referenced to total drug concentration in the plasma was 1.31 +/- 0.07 liters, approximately the plasma volume, due to the high protein binding of 97%. The mean metabolic clearance of drug in the plasma was 124 +/- 3.8 ml/min, half of the hepatic plasma flow, but was 4131 +/- 690 ml/min referenced to unbound drug concentration in the plasma, 16.5 times the hepatic plasma flow, indicating that net metabolism of both bound and unbound drug occurs. Apparent parallel production of several metabolites occurred, but the pharmacokinetics of their appearance were undoubtedly due to their sequential production during liver passage. The apparent half-life of the metabolic process was 6.9 +/- 0.3 min. The terminal half-life of delta9-tetrahydrocannabinol in the pseudo-steady state after equilibration in an apparent overall volume of distribtuion of 2170 +/- 555 liters referenced to total plasma concentration was 8.2 +/- 0.23 days, based on the consistency of all pharmacokinetic data. The best estimate of the terminal half-life, based only on the 7000 min that plasma levels could be monitored with the existing analytical sensitivity, was 1.24 days. However, this value was inconsistent with the metabolite production and excretion of 40-45% of dose in feces, 14-16.5% in urine, and 55% in bile within 5 days when 24% of the dose was unmetabolized and in the tissue at that time. These data were consistent with an enterohepatic recirculation of 10-15% of the metabolites. Intravenously administered radiolabeled metabolites were totally and rapidly eliminated in both bile and urine; 88% of the dose in 300 min with an apparent overall volume of distribution of 6 liters. These facts supported the proposition that the return of delta9-tetrahydrocannabinol from tissue was the rate-determining process of drug elimination after initial fast distribution and metabolism and was inconsistent with the capability of enzyme induction to change the terminal half-life.

Animals↗
PubMed1977

Kinetics and mechanisms of monolayer interactions IV: Surface activity of alkanols and energies of their interaction with dipalmitoyllecithin and dipalmitoylphosphatidylethanolamine.

The free energies of adsorption of the C1 to C14 alkanols at the air--water interface, estimated from plots of the surface pressure (pi less than or equal to 5 dynes/cm) against the bulk concentration, were a linear function of the chain length for 1-alkanols. From C3 to C8, the 2- and 3-isomers showed lower values than the 1-isomers. The energies of interaction of the C1 to C14 alkanols with dipalmitoylphosphatidylethanolamine and dipalmitoyllecithin monolayers, previously spread at the air-water interface, were estimated from the increase of the surface pressure with increasing concentrations of the injected alkanol. The energies of interaction of the C1 to C5 1-alkanols were linear functions of the chain length. The energy of interaction per methylene group of the alkyl chain suggests that the phospholipid monolayers behaved as ultrathin "oil" phases. The 2- and 3-isomers presented marked departures from linearity. The literature data for reflection coefficients in biomembranes and for partition coefficients between olive oil and water, red cell membranes and water, and phospholipid liposomes and water for the C1 to C5 alkanols show similar linearities with the chain length for the 1-isomers and comparable departures for the 2- and 3-isomers.

Adsorption↗
PubMed1977

Correction of prior estimate of the biological activity of an N-trifluoroacetyl analogue of D-threo-chloramphenicol relative to chloramphenicol.

The inhibitory rate constants, k, for the inhibition of the rate of Escherichia coli generation at various concentrations, C, of chloramphenicol nad its N-trifluoroacetyl analogue were determined in vitro in accordance with kapp = k0 - kC where kapp is the apparent first-order generation rate constant at a drug concentration C and k0 is that constant in the absence of drug. The activity of the analogue was one-tenth that of chloramphenicol in contrast to a previously reported value.

Chloramphenicol↗
PubMed1976

[Clinical pharmacokinetics].

The action of a drug depends on the quantity which reaches the site of its pharmacological action and how long it remains there. The necessary vital processes of the body dilute the active principle into different compartments of distribution, transform it into metabolites, and excrete it. Since a time duration of drug presence at the site of action is vital for the cure of disease, a comprehensive and quantitative expression of these time courses of drug distribution as a function of dose and route of administration is necessary for the establishment of proper dosage regimens for the treatment of disease and the avoidance of toxicities. The purpose of pharmacokinetics is to study these phenomena and to construct models suitable to explain them and to predict the behavior of drugs in conditions not yet studied. In this review some basic principles of pharmacokinetics (i.e. the compartment, the volume of distribution, the elimination half-life, etc.) are explained. Their clinical implications are shown in the case of multiple dose administration and in the study of the relations existing between blood levels of digoxin and the pharmacological action of this drug.

Body Weight↗
PubMed1976

Separation and sensitive assay of THC in biological fluids by HPLC and GLC.

HPLC systems were developed to permit quantitative separation of delta9-tetrahydrocannabinol from many of the heptane extractable lipoidal and other endogenous substances in biological fluids. These substances interfered with the quantification by flame ionization GLC of unmodified compound and by electron capture GLC of pentafluorobenzoylated compound. Reverse phase HPLC elution, with 47% acetonitrile in water, and normal phase HPLC with 25% chloroform in heptane, separated tetrahydrocannabinol from 11-hydroxy-delta9-tetrahydrocannabinol and other monohydroxylated tetrahydrocannabinols. These systems also purified stock solutions of tetrahydrocannabinol from accompanying contaminants. The various monohydroxylated tetrahydrocannabinols were resolved from each other in normal phase, 80% chloroform in heptane. The delta8 and delta9-tetrahydrocannabinols were separable in normal phase with 5% tetrahydrofuran in hexane. The GLC analysis of pentafluorobenzoylated tetrahydrocannabinol had a sensitivity of 1 ng/ml of plasma with an estimated 5% standard error of an assay with the extraction and GLC procedures given herein. Radiochemical analysis of the HPLC separated fraction had s sensitivity of 0.2 ng/ml of plasma with an estimated 2% standard error of an assay. There was no significant difference between the liquid scintillation and electron capture GLC assays of the HPLC separated delta9-tetrahydrocannabinol obtained from the plasma of dogs administered the drug. Radiolabelled compounds can be added to plasma samples as internal standards to determine the recovery efficiencies of the several procedures in the analysis of unlabelled tetrahydrocannabinol.

Animals↗
PubMed1975

Kinetics and mechanisms of monolayer interactions. III: models to explain time-dependent effects of injected cetrimonium bromide.

Two kinetic models are derived to explain the time-dependent effects of cetrimonium ions injected beneath an air-aqueous solution interface without any previously adsorbed or spread monolayer at different ionic strengths. The data show excellent fit and consistency with a nulticompartmental kinetic model which postulates a barrier or intermediate compartment between the ionic surfactant in the subphase and the sites on the surface. Such a barrier inhibits free diffusion of the surfactant from the bulk of the solution to these sites. The experimental data are not inconsistent with a model that postulates a time-dependent binding process and the absence of a diffusion-limiting subinterface since, within the limits of the error, the derived rate constants conform to the model prediction that they should be proportional to the surfactant-ion concentration.

Adsorption↗
PubMed1975

Kinetics and mechanisms of drug action on microorganisms XXII: Effects of aminosidine with and without organism pretreatment with bacteriostatic agents.

Escherichia coli generation in the logarithmic growth phase was inhibited in peptone broth USP at pH 7.0 without kill below 3.0 mug/ml of aminosidine. Above this value, the logarithms of the number of viables of the drug-treated culture ultimately decreased linearly with time and the slopes of these plots were independent of concentration. A concentration-dependent lag in the time of attainment of the cidal action was observed, and the extent of this lag was related to the ease of emergence of resistant organisms. The minimal concentration for cidal action increased with increasing concentrations of nutrients and with decreasing pH. Pretreatment of the cultures with novobiocin and tetracycline lessened the minimum bactericidal concentration of aminosidine whereas chloramphenicol pretreatment increased it. Tetracycline pretreatment inhibited the emergence of aminosidine-resistant organisms.

Anti-Bacterial Agents↗