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Biomedical subjects

D R Abernethy

Publications and source records attributed to D R Abernethy.

At least 199 records · Page 11Linked to original sources
PubMed1981

Digoxin disposition in obesity: clinical pharmacokinetic investigation.

Digoxin pharmacokinetics were studied in 16 obese (mean +/- SD weight, 100.2 +/- 36.8 kg) and 13 control (64.6 +/- 10.5 kg) subjects. All subjects had normal renal function and no other coexisting disease. After administration of 0.75 mg digoxin by intravenous infusion, multiple plasma samples obtained over the 96 hours following infusion were analyzed for digoxin concentration by radioimmunoassay. Pharmacokinetic parameters were determined by weighted iterative nonlinear least squares regression analysis. Elimination half-life (t 1/2) was not different between obese and control groups (35.6 +/- 10.5 vs 41.2 +/- 16.7 hours). Absolute volume of distribution (Vd) also was not different (981 +/- 301 vs 937 +/- 397 liters), nor was total clearance of digoxin (328 +/- 82 vs 278 +/- 87 ml/min). Elimination t 1/2 was significantly negatively correlated with clearance among all subjects (r = -0.46; p less than 0.01). Using percent ideal body weight (IBW) as a measure of obesity, no correlation was found between percent IBW and Vd (r = 0.03). Thus digoxin is similarly distributed into IBW in obese and normal weight subjects, and there is no significant distribution of digoxin into excess body weight over IBV. In addition, there is no difference in total metabolic clearance or elimination half-life between obese and control subjects. Digoxin loading and maintenance dosage should be calculated on the basis of IBW, which reflects lean body mass, rather than TBW, which reflects adipose tissue weight in addition to lean body mass.

Adult↗
PubMed1981

Effects of desmethyldiazepam on diazepam kinetics: a study of effects of a metabolite on parent drug disposition.

The effect of high concentrations of desmethyldiazepam (DMDZ), the major metabolite of diazepam (DZ), on parent drug kinetics was evaluated in six healthy young subjects who received a single intravenous dose (10 mg) of DZ on two occasions. The first DZ dose was given in the drug-free control condition and the second after the subject had ingested clorazepate (CZP), a precursor of DMDZ (15 mg daily for 7 days before DZ and then during the second DZ study). Maximum DMDZ concentration after the first DZ dose did not exceed 66 ng/ml, whereas mean DMDZ levels (derived from CZP) during the second DZ study were 481 +/- 61.5 ng/ml (SE) for all subjects. DZ kinetic parameters for all subjects during the first and second studies were: elimination half-life (t 1/2), 43.3 +/- 5.3 and 44.9 +/- 9.7 hr; total volume of distribution (Vd), 1.26 +/- 0.10 and 1.32 +/- 0.10 l/kg; unbound Vd, 97.4 +/- 9.9 and 94.9 +/- 9.9 l/kg; clearance, 0.364 +/- 0.048 and 0.394 +/- 0.055 ml/min/kg; and unbound clearance, 28.3 +/- 4.6 and 28.3 +/- 5.0 ml/min/kg. Percent unbound DZ was 1.40 +/- 0.25% when subject plasma was spiked with DZ alone and 1.47 +/- 0.21% when subjects' plasma was spiked with 500 ng/ml DMDZ in addition to DZ. Paired analysis of the two studies in each subject revealed no difference in t 1/2, Vd, unbound Vd, clearance, or DZ protein binding in the absence or presence of DMDZ. Formation and presence of the active metabolite DMDZ had no influence on kinetic behavior of parent DZ.

Adult↗
PubMed1981

Impairment of antipyrine metabolism by low-dose oral contraceptive steroids.

The effect of low-dose oral contraceptive steroids (OCS) on the kinetics of intravenous antipyrine was determined. Eight women (age, 23.1 +/- 1.1 yr (mean +/- SE); weight, 57.8 +/- 2.2 kg) using low-dose (less than or equal to 50 micrograms) estrogen oral contraceptive steroids (OCS) on a long-term basis were age- and weight-matched with eight controls (age, 23.4 +/- 0.8 yr; weight, 58.4 +/- 2.1 kg) not using OCS. All were nonsmokers taking no other drugs. OCS subjects had a longer antipyrine elimination half-life (t1/2 beta) than the controls (17.3 +/- 1.6 and 10.5 +/- 0.8 hr; p less than 0.005). Volume of distribution was similar for both groups (0.59 +/- 0.02 l/kg [OCS] and 0.58 +/- 0.02 l/kg). Total metabolic clearance of antipyrine was slowed in OCS subjects (0.41 +/- 0.03 and 0.66 +/- 0.05 ml/min/kg; p less than 0.001). Since volume of distribution and body weight are of the same order in both groups, prolongation of antipyrine t1/2 beta is the result of decreased total metabolic clearance. Thus, even low-dose estrogen containing OCS may impair clearance of other drugs.

Adult↗
PubMed1981

Diazepam kinetics in patients with renal insufficiency or hyperthyroidism.

1 Eight patients with end-stage renal insufficiency on maintenance haemodialysis, and seven patients with newly diagnosed hyperthyroidism, received a single intravenous dose of diazepam, followed by blood sampling over the next 7 days. Fifteen healthy volunteer controls, matched with patients for age and sex, were similarly studied. 2 Diazepam half-life in renal failure patients (mean 37 h) was greatly reduced compared to controls (mean 92 h, P less than 0.05) and clearance of total (free plus bound) diazepam correspondingly increased (0.94 v 0.34 ml min-1 kg-1, P less than 0.01). 3 However, differences were largely related to disease-related changes in drug binding and distribution. Mean unbound fraction of diazepam in plasma of renal patients (7.0%) was greatly increased over controls (1.4%, P less than 0.01) and Vd of unbound diazepam greatly reduced (57 v 157 l/kg, P less than 0.01). 4 Clearance of pharmacologically active unbound diazepam (intrinsic clearance) was not significantly different between renal patients and controls (23 vs 30 ml min-1 kg-1). 5 None of the kinetic variables for total or unbound diazepam in thyrotoxic patients differed significantly from those in controls matched for age and sex. 6 End-stage renal failure (or its associated drug therapy) alters diazepam protein binding and distribution, but does not significantly change clearance of unbound drug. Thyrotoxicosis does not influence diazepam kinetics.

Diazepam↗
PubMed1981

Diazepam kinetics in relation to age and sex.

27 male volunteers aged 20 to 91 years, and 13 female volunteers aged 21 to 33 years, received single 5 to 10 mg doses of diazepam intravenously. Diazepam pharmacokinetics were determined from concentrations measured in multiple plasma samples drawn during 7 days after each dose. Diazepam elimination half-life among males (mean: 66 h) increased significantly with age (r = 0.53, p less than 0.005). Volume of distribution (mean: 1.39 liters/kg) also increased significantly with age (r = 0.67, p less than 0.001). Clearance of total diazepam in males (mean: 0.42 ml/min/kg) tended to decline with age (r = 0.32), but the association was of borderline significance (p = 0.1). Diazepam was extensively bound to plasma protein, with a mean free fraction among male subjects of 1.34%. Free fraction tended to increase with age (r = 0.14). Correction of volume of distribution and clearance for individual differences in binding did not alter the conclusions. Compared to young males, young females had larger volumes of distribution (1.87 vs. 1.34 liters/kg) and higher total clearance (0.63 vs. 0.49 ml/min/kg). These differences were even greater after correction for sex-related changes in protein binding. Elimination half-life did not differ between sexes. Since both age and sex can influence diazepam disposition, both should be considered as independent variables in studies of diazepam pharmacokinetics.

Adult↗
PubMed1981

Tricyclic antidepressant determination in human plasma by gas-liquid chromatography using nitrogen-phosphorous detection: application to single-dose pharmacokinetic studies.

A method with adequate sensitivity (to 0.50-0.75 mg/ml) for single-dose pharmacokinetic studies which utilizes gas-liquid chromatography with nitrogen-phosphorous detection for tricyclic antidepressants (imipramine, desipramine, amitriptyline, nortriptyline, and doxepin) is described. A basic (pH 13) extraction with acid back-wash and subsequent basic reextraction is used for plasma sample preparation. Standard curves, using clomipramine as the internal standard, are linear for concentrations from 1 to 200 ng/ml for all tricyclic antidepressants. Applicability of the method is demonstrated by a pharmacokinetic study in a normal volunteer who received 12.5 mg imipramine hydrochloride i.v.

Antidepressive Agents, Tricyclic↗
PubMed1978

Use of saliva lithium determinations for monitoring lithium therapy.

During acute and chronic administrations of lithium, 25 patients were studied to determine the effect of other psychotropic drugs on the plasma-saliva lithium concentration correlations. Changes, even discontinuation, in either tricyclic antidepressants or neuroleptics did not affect the plasma-saliva ratio which had an overall correlation coefficient of r = 0.79 (p less than 0.01). The relationship using linear regression analysis was described by the equation, y = 2.27x--0.45. Individual patients' plasma-salivary relations were described by this equation in 87% of cases. The study extends the usefulness of these determinations to include patients on lithium and neuroleptics or tricyclic antidepressants.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

Physiological pharmacokinetics and pharmacodynamics of (+/-)-verapamil in female rats.

Tissue distribution and pharmacodynamics of verapamil were evaluated during steady state intravenous (i.v.) infusion and after single dose intraperitoneal (i.p.) drug administration to female Sprague-Dawley rats. In one group of rats, verapamil was infused to a steady state concentration at which time animals were killed. Verapamil-induced decreases in mean arterial pressure (MAP) were monitored during infusion and correlated with concomitantly obtained plasma verapamil concentrations. Tissue (lung, liver, renal medulla, renal cortex, cardiac muscle, skeletal muscle, perirenal fat, brain stem, cerebral cortex, and cerebellum) and plasma samples were obtained immediately after animals were killed and verapamil and norverapamil concentrations determined. Another group of rats, after receiving i.p. verapamil, were killed at 1, 3, 5, 19, and 24 h. Elimination from each tissue evaluated was described by a first order process. Elimination half-life of verapamil was similar among plasma and tissues evaluated (1.5 to 2.2 h). The per cent verapamil not bound to plasma proteins was concentration-independent and similar between rats receiving i.p. (mean +/- S.D.) (2.28 +/- 0.72 per cent) and i.v. (2.08 +/- 0.03 per cent) verapamil. MAP and verapamil concentration in plasma (r = 0.75; p less than 0.01) and cardiac muscle (r = -0.82; p less than 0.01) were inversely correlated in a highly significant fashion during both i.v. and i.p. drug administrations. The tissue-to-plasma distribution ratio for verapamil and norverapamil was similar among animals receiving i.p. verapamil at all points of sampling, suggesting distribution equilibrium had been achieved. After steady state i.v. infusion, both verapamil and norverapamil tissue: plasma concentration ratios were greater than after i.p. administration. Higher tissue: plasma verapamil concentration ratios after i.v. administration than after i.p. administration suggest either only a pseudoequilibrium is attained after i.p. administration or that determinants of tissue distribution of racemic verapamil differ with different routes of drug administration. In these studies, MAP provided a reasonable pharmacodynamic marker for verapamil tissue and plasma concentrations.

Animals↗
PubMedDate not supplied

Effect of food on acetaminophen absorption in young and elderly subjects.

Twenty-four healthy volunteers aged 22 to 78 years received 650-mg doses of acetaminophen (AAP) on five separate occasions. The modes of administration were: intravenous AAP by 5-minute infusion; oral AAP as two 325-mg tablets in the fasting state; oral AAP 650 mg as an elixir preparation in the fasting state; tablets with food; and elixir with food. Plasma concentrations of AAP were determined by high-pressure liquid chromatography for up to 12 hours after the dose. In both the young and the elderly groups, the four oral modes of administration were significantly different with respect to peak plasma concentration (P less than 0.001), time to peak plasma concentration (P less than 0.001), and systemic availability (P less than 0.01). Although food slowed the rate of absorption of both oral preparations, no significant difference in peak acetaminophen plasma concentration or time of peak concentration was observed as a function of age. Absolute systemic availability of elixir and tablets in the fasting state tended to be lower in the elderly subjects (P less than 0.05). However, when either preparation was coadministered with food, there were no differences between the two age groups. Thus, age as such does not appear to be a critical determinant in the design of oral acetaminophen dosage schedules.

Absorption↗
PubMedDate not supplied

Ibuprofen does not impair antipyrine clearance.

The influence of therapeutic doses of ibuprofen on the distribution and clearance of antipyrine in humans was evaluated in a series of healthy volunteers. Subjects received a single intravenous dose of antipyrine on two occasions, once in the drug-free control state and again during coadministration of ibuprofen, 1.6 to 2.4 Gm per day in divided doses. Compliance was verified by measurement of plasma ibuprofen levels, which averaged 22 micrograms/ml. Kinetic variables for antipyrine were determined from multiple plasma antipyrine concentrations measured during 24 hours after each dose. Between drug-free control and ibuprofen coadministration trials, there was no significant difference in antipyrine volume of distribution (0.69 vs. 0.69 liter/kg), elimination half-life (12.2 vs. 12.5 hours), or total metabolic clearance (0.69 vs. 0.70 ml/min/kg). Thus, ibuprofen does not impair the clearance of the marker compound antipyrine, often used as an index of drug oxidizing capacity in humans.

Adult↗
PubMedDate not supplied

Prolonged accumulation of diazepam in obesity.

Six obese (mean weight 92 kg) and five normal (60 kg) subjects received 2 mg diazepam nightly for 30 nights. Determination of diazepam and desmethyldiazepam plasma concentrations during the dosing period and for a withdrawal period indicated that accumulation half-life for both diazepam (7.8 days in obese vs. 3.1 days in normal subjects, P less than 0.05) and desmethyldiazepam (30.3 vs. 7.2 days, P less than 0.05) was markedly prolonged in obese subjects. However, mean steady-state plasma concentrations of diazepam (68 vs. 67 ng/ml) and desmethyldiazepam (156 vs. 91 ng/ml) did not significantly differ between groups. To determine the basis for this delay in accumulation in obese subjects, single-dose pharmacokinetics of diazepam and desmethyldiazepam were determined. Diazepam elimination half-life was greatly prolonged in the obese subjects (82 vs. 32 hours, P less than 0.005), with no change in total metabolic clearance (32 vs. 26 ml/min). Instead, a large increase in volume of distribution (228 vs. 70 liters, P less than 0.01) was the reason for prolongation of the elimination half-life. Similarly for desmethyldiazepam, elimination half-life was prolonged in obese subjects (130 vs. 56 hours, P less than 0.01), without a change in total metabolic clearance (13.7 vs. 19.2 ml/min), due to increased volume of distribution (151 vs. 73 liters, P less than 0.01). During chronic dosing with diazepam, obese patients may experience a much slower onset of maximal drug effect compared to normal-weight patients because of the greatly delayed accumulation of diazepam and desmethyldiazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗