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Biomedical subjects

R A Morrison

Publications and source records attributed to R A Morrison.

At least 37 records · Page 2Linked to original sources
PubMed1990

Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects.

Pravastatin sodium, a competitive inhibitor of HMG-CoA reductase, is a new orally effective hypocholesterolaemic agent. In a two-way crossover study, eight healthy male subjects each received an intravenous and an oral dose of [14C]-pravastatin sodium. The oral absorption of [14C] activity from pravastatin sodium was about 34% and the oral bioavailability was about 18%, suggesting first-pass metabolism of pravastatin. After the intravenous dose, the recovery of radioactivity averaged 60% and 34% in urine and faeces, respectively. Corresponding values were 20% (urine) and 71% (faeces) for the oral dose. The estimated average plasma elimination half-life of pravastatin was 0.8 and 1.8 h for the intravenous and oral routes, respectively. The average values for total and renal clearances were 13.5 and 6.3 ml min-1 kg-1, respectively, and the steady-state volume of distribution averaged 0.51 kg-1. These results suggest that both kidney and liver are important sites of elimination for pravastatin.

Administration, Oral↗
PubMed1988

Dose proportionality of nadolol pharmacokinetics after intravenous administration to healthy subjects.

To support the increasing use of intravenous beta-blockers during cardiovascular emergency and surgery, dose proportionality of pharmacokinetics of nadolol was evaluated after intravenous administration of 14C-nadolol at doses of 1, 2 and 4 mg to nine healthy volunteers. There were no observed differences in the excretion or the pharmacokinetics of nadolol with respect to the dose administered. Over a 72-h period after drug administration, an average of about 60% of the dose was excreted in the urine and about 15% was excreted in the feces. The range of values for total body clearance (219 to 250 ml.min-1), renal clearance (131 to 150 ml.min-1), mean residence time (10.5 to 11.3 h), half-life (8.8 to 9.4 h), and steady-state volume of distribution (Vss) (147 to 157 l) indicated that nadolol was extensively distributed and slowly cleared from the body. There was a linear correlation (r2 = 0.97) between the area under the plasma concentration of nadolol versus time curve (AUC) and the dose. All pharmacokinetics parameters, except Vss, were slightly, but significantly, different at the 4 mg dose. Superposition of the dose-normalized average concentrations indicated that despite these minor differences in parameters, the pharmacokinetic behavior of nadolol was linear with respect to dose. Urinary excretion of nadolol was dose independent.

Adult↗
PubMed1988

Pharmacokinetics of intravenous captopril in healthy men.

The pharmacokinetic characteristics of intravenously-administered captopril were investigated in 7 healthy men 20 to 33 years old. Capropril, labeled with 14C, was given by injection over a 1 min period at mean doses of 2.78 mg (13.8 microCi), 5.67 mg (28.2 microCi) and 11.4 mg (56.8 microCi). Concentrations of unchanged captopril, captopril disulfide, and other metabolites (collectively) were determined in body fluids. Pharmacokinetic parameters were calculated for unchanged captopril, and it was shown that the disposition of intravenously-administered drug was linear with respect to dose over the dosage range studied.

Adult↗
PubMed1988

Disposition of fosinopril sodium in healthy subjects.

1 Fosinopril sodium is the first phosphorus-containing angiotensin-converting enzyme (ACE) inhibitor to be studied clinically as an antihypertensive agent. It is an ester prodrug that is hydrolysed in vivo to the active diacid ACE inhibitor, SQ 27, 519. 2 In a three-way crossover study, nine healthy male subjects (age range 20-34 years) each received an intravenous 7.5 mg dose of SQ 27, 519-[14C] and two oral 10 mg doses of [14C]-fosinopril sodium, administered as a capsule and in solution. 3 After the intravenous dose of SQ 27, 519, the 0 to 96 h recovery of radioactivity averaged 44 and 46% of the dose in urine and faeces, respectively, indicating substantial biliary secretion. Only intact SQ 27, 519 was detected in the plasma, urine, and faeces following the intravenous dose of SQ 27, 519. 4 After oral doses of fosinopril sodium, about 75% of the radioactivity in plasma and urine was present as SQ 27, 519; the remainder corresponded mainly to a beta-glucuronide conjugate of SQ 27, 519 (15-20%), and a monohydroxylated analogue of SQ 27, 519 (about 5%). Negligible amounts of fosinopril sodium were present, indicating complete hydrolysis of the prodrug. 5 For the solution and capsule doses, respectively, the oral absorption of fosinopril sodium averaged 32% and 36% and the oral bioavailability of SQ 27, 519 averaged 25% and 29%. 6 The average values for clearance (39 ml min-1), renal clearance (17 ml min-1), Vss (10 1), and plasma protein binding (approximately 95%), indicated that SQ 27, 519 was slowly cleared from the body and not distributed extensively into extravascular sites.

Administration, Oral↗
PubMed1987

Relationship between metabolism and pharmacologic activity of SQ 27,786, an angiotensin converting enzyme inhibitor with potent diuretic activity.

SQ 27,786 is a sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor, which also possesses potent diuretic activity in dogs after intravenous administration. The absorption, distribution, metabolism and elimination of 35S-labeled SQ 27,786 was studied in dogs to determine if the observed pharmacologic activities were intrinsic to this compound or the result of metabolism to separate ACE-inhibitory and diuretic moieties. The poor pharmacologic activity observed after oral administration was found to be due to poor absorption of the ACE-inhibitory-diuretic compound. The results of this study indicated that SQ 27,786 was excreted largely intact, either as the parent compound, the symmetrical disulfide of the parent compound, or as mixed disulfides of the parent compound with endogenous sulfhydryl compounds (e.g., SQ 27,786-L-cysteine) in a manner similar to captopril. It was concluded that the observed diuretic and ACE inhibitory activities were the result of intact SQ 27,786 and not of metabolites resulting from cleavage of the molecule to separate diuretic and ACE inhibitory moieties.

Angiotensin II↗
PubMed1984

Determination of the partitioning, stability, and metabolite formation of isosorbide dinitrate in human and rat blood using an improved gas-liquid chromatographic assay.

A simple and highly sensitive gas-liquid chromatographic method using electron-capture detection has been developed for the simultaneous determination of isosorbide dinitrate (ISDN) and its mononitrate metabolites in rat and human plasma. This method has a limit of quantitation of about 5 ng/ml for the mononitrates and of 1 ng/ml for ISDN using 0.1 ml of plasma, and is thus useful for pharmacokinetic studies of these compounds in small animals, and in humans when the available volume of blood is limited. Using this method, we found the apparent in vitro partitioning ratio of ISDN between erythrocyte and plasma in rat and human blood at 37 degrees C to be 0.22 and 0.13, respectively. In spite of this poor affinity for red blood cells, ISDN degradation in whole blood was mediated primarily via this blood fraction. Loss of ISDN in blood appeared to proceed exclusively through its mononitrate metabolites, resulting in a 6:1 product ratio of the 5-mononitrate to its 2-isomer. These data suggest that although blood degradation of ISDN and erythrocyte partitioning occur per se, these phenomena do not contribute significantly to the very rapid in vivo clearance of ISDN observed in man and in the rat.

Animals↗
PubMed1984

Isosorbide dinitrate disposition in the rat: metabolite pharmacokinetics and interactions.

The pharmacokinetics of isosorbide dinitrate (ISDN) and its isomeric mononitrate metabolites (2- and 5-ISMN) were examined in the rat. At a dose of 2 mg/kg, the oral bioavailability of ISDN was found to be about 40%. This finding corrects a previous belief that organic nitrates, when administered via the oral route, are completely metabolized by hepatic first-pass metabolism. ISDN was metabolized exclusively via its mononitrate metabolites, with the 5-ISMN being the principal product (about 90%). The ratio of 2- to 5-ISMN produced was dependent on the route of administration, being 0.18 +/- 0.03 after i.v. dosing and 0.11 +/- 0.03 after oral dosing (both mean +/- S.D.). 2-ISMN was found to decrease the plasma clearance of ISDN; this metabolite interaction occurred when drug and metabolite were administered either at the same or different intravascular sites. 5-ISMN did not affect ISDN plasma clearance when these compounds were administered at different intravascular sites. However, when 5-ISMN and ISDN were given at the same vascular site, a decrease in plasma ISDN clearance was observed. These results provide an interesting example of divergent pharmacokinetic interactions exhibited by two isomeric metabolites.

Animals↗
PubMed1983

Isosorbide dinitrate kinetics and dynamics after intravenous, sublingual, and percutaneous dosing in angina.

Isosorbide dinitrate (ISDN) kinetics and dynamics were examined after various routes of administration for angina. Given intravenously, ISDN kinetics were apparently linear over the range of infusion rate (0.083 and 0.133 mg/min) and duration (15 min and 1 and 2 hr) studied. Mean +/- SD systemic clearance of ISDN was 3.4 +/- 1.4 l/min and volume of distribution (VdSS or Vdarea) about 100 l. These data are consistent with the presence of extensive extrahepatic metabolism. In six patients, sublingual ISDN (5 mg) was also given and mean bioavailability of 59% (19% to 93%) for this route was determined. For this group, sublingual absorption of intact ISDN was incomplete and variable. The presence of a longer disappearance t 1/2 after sublingual dosing suggested that the input process may be rate limiting. After percutaneous application of a topical formulation (100 mg over an area of 400 cm2), steady-state plasma concentrations at about 7 ng/ml were maintained from 6 to 24 hr. The bioavailability of the topical application was estimated at 30%. At the doses given, intravenous ISDN had no apparent effect on heart rate but induced significant reduction in standing systolic blood pressure. The effect vs the ISDN concentration profile was described by a hysteresis loop, indicating that changes in blood pressure response lag behind changes in plasma ISDN concentration. After intravenous dosing, peak plasma ISDN concentration and peak effect (maximum change in standing systolic blood pressure). At the doses used, both sublingual and percutaneous ISDN induced less distinct circulatory changes than the intravenous infusion.

Absorption↗
PubMed1983

Hepatic extraction of isosorbide dinitrate in cardiac patients.

Hepatic extraction of organic nitrates, including that of isosorbide dinitrate (ISDN), has been thought to be nearly complete in man but has never been directly measured. We examined the time course of plasma ISDN and metabolite concentrations in arterial and hepatic venous blood in four cardiac patients receiving an intravenous ISDN infusion. Apparent hepatic extraction of ISDN was high (90%) at the beginning of infusion but fell to about 44% 1 hr after termination of infusion. The decrease in ISDN concentration gradient across the liver correlates with an increase in plasma isosorbide-5-mononitrate concentration, but a cause-and-effect relationship resulting from metabolite inhibition cannot be established. The time-averaged hepatic extraction of ISDN, at about 70%, agreed with its oral bioavailability in patients.

Biological Availability↗
PubMed1978

Spherical lead shields for megavoltage teletherapy.

A new method of manufacturing individualized, focused lead shields for megavoltage teletherapy is described. Computerized film dosimetry demonstrated that in contrast to nonfocused shields, the new focused shields exhibit good maintenance of penumbra width as the distance between the edge of the beam and the central axis is increased.

Humans↗
PubMed1975

The total biological dose.

The nominal standard dose concept is used to define the total biological dose or cumulative radiation effect at a point for treatment regimens employing two or more radiation modalities. Various clinical applications are illustrated. A convenient nomographic method for determining the total biological dose is presented.

Cobalt Radioisotopes↗
PubMed1975

A drop-in treatment shell support.

An easily made, inexpensive drop-in support for the use with treatment shells fabricated by the direct (plaster of paris bandage) method is used to immobilize the patient and reproduce the treatment position. Its quick and easy method of attachment and removal requires a minimum of patient cooperation.

Head↗
PubMed1975

The radius-dose relationship in linear source therapy.

The rationale and physical data are presented which support the hypothesis that the tolerance dose on the surface of a cylindrical applicator containing a central linear source is inversely proportional to the cube root of its radius.

Dose-Response Relationship, Radiation↗