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Biomedical subjects

D R Abernethy

Publications and source records attributed to D R Abernethy.

At least 109 records · Page 6Linked to original sources
PubMed1986

Influence of age, gender, and obesity on salicylate kinetics following single doses of aspirin.

Salicylate kinetics following single, 650-mg intravenous and oral doses of aspirin were evaluated in humans in 2 studies. Complete conversion of aspirin to salicylate was assumed. The first study involved 25 young (25-40 years) and 21 elderly (66-89 years) healthy male and female volunteers. Mean salicylate clearance was lower in elderly females compared with that in young females; however, the difference between young men and elderly men was not significant. Salicylate free fraction in plasma increased significantly with age in men and women. After correction for free fraction, unbound mean clearance was reduced in elderly men compared with young men, and in elderly women compared with young women. Peak plasma salicylate concentrations after taking oral aspirin were not significantly influenced by age, and systemic availability of salicylate in all groups was complete. The second study compared 20 obese subjects (mean weight 113 kg) with 20 normal weight controls (mean weight 67 kg) matched for age, sex, height, and smoking habits. Small differences between obese and control groups were observed in total salicylate volume of distribution (Vd), unbound Vd, and mean clearance of total or unbound salicylate. Following normalization for total weight, however, values of total Vd and mean clearance were significantly smaller in obese subjects than in normal weight subjects. Rate and completeness of salicylate absorption were not influenced by obesity when aspirin was ingested, although peak levels were lower in obese subjects. If applied to multiple doses, the reduced unbound clearance of salicylate in the elderly would imply increased accumulation unless doses are appropriately adjusted downward. During long-term therapy, salicylate dosage for obese individuals should not be adjusted upward in proportion to total weight.

Administration, Oral↗
PubMed1986

The pharmacokinetics of diazepam and desmethyldiazepam in rat brain and plasma.

The pharmacokinetics of diazepam (DZ) and its major metabolite desmethyldiazepam (DMDZ) in both plasma and brain after a single 5 mg/kg IP dose of diazepam were studied in rats. Four rats were sacrificed at 5 min, 15 min, 30 min, 1 h, 1.5, 2, 3, 4, 5 and 6 h after the dose. DZ rapidly disappeared from plasma and brain in parallel, with nearly identical overall half-lives of 0.88 and 0.89 h, respectively. Apparent volume of distribution was 19.3 1/kg and the apparent total clearance was 255 ml/kg/min. Free fractions were 19.6% and 15.8% for DZ and DMDZ, respectively. DMDZ rapidly appeared in both plasma and brain. Thereafter, DMDZ was likewise eliminated in parallel from both compartments, with nearly identical half-lives of disappearance from plasma (1.11 h) and brain (1.09 h). The rapid elimination of DZ was due to its very high clearance. Brain to plasma concentration ratios did not differ significantly over time either for DZ or for DMDZ. The overall ratios (mean +/- SE) were 4.5 +/- 0.1 for DZ and 3.5 +/- 0.2 for DMDZ. Equilibrium was attained at no more than 5 min after dose for both DZ and DMDZ. No evidence was found for persistence or sequestration of DZ or DMDZ in brain longer than could be predicted on the basis of first-order exponential disappearance.

Animals↗
PubMed1986

Diltiazem treatment impairs hepatic drug oxidation: studies of antipyrine.

To evaluate the effect of diltiazem on antipyrine disposition and metabolism, 10 healthy subjects received 1.2 gm antipyrine on two occasions, once while taking no other medications and once during long-term oral diltiazem, 120 mg three times daily. Antipyrine oral clearance was markedly reduced from (mean +/- SEM) 41.7 +/- 4.1 to 29.9 +/- 2.8 ml/min (P less than 0.01) during diltiazem treatment, resulting in prolongation of antipyrine elimination t1/2 from 12.2 +/- 1.0 to 16.7 +/- 1.3 hours (P less than 0.01), with no change in apparent volume of distribution (42.1 +/- 4.0 vs. 41.3 +/- 3.1 L; not significant). Measurement of urinary antipyrine and metabolites excreted in the urine during 24 hours after the antipyrine dose (percent of total 24-hour excretion) showed increased antipyrine (4.4% +/- 1.0% vs. 7.8% +/- 1.6%; P less than 0.01) during diltiazem treatment with no significant change in proportion of 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine excretion between trials. Chronic oral diltiazem in therapeutic doses markedly impairs antipyrine oxidation. Diltiazem may therefore impair the clearance of other coadministered drugs that undergo hepatic oxidation.

Administration, Oral↗
PubMed1986

Obesity effects on nitrazepam disposition.

Nitrazepam pharmacokinetics were studied in 14 obese (mean +/- s.e. mean body weight 107 +/- 9 kg; percent ideal body weight [IBW] 166 +/- 12%) and 14 normal body weight (63 +/- 3 kg; percent IBW 98 +/- 2%) subjects. After an overnight fast, each subject ingested 10 mg nitrazepam orally. Nitrazepam concentrations were determined in plasma samples obtained over the following 72 h. Comparison of peak nitrazepam plasma concentration (94.2 +/- 10.3-obese vs 119 +/- 14.6 ng ml-1; NS) and time required after drug administration to reach peak concentration (1.52 +/- 0.24-obese vs 1.59 +/- 0.36 h; NS) indicated no differences between obese and control subjects. Elimination half-life was markedly increased in obese subjects (33.5 +/- 2.2 vs 23.9 +/- 1.2 h; P less than 0.001) due to increased apparent volume of distribution (Vd) (290 +/- 45 vs 137 +/- 12 l; P less than 0.005). Oral clearance was also increased in the obese subjects (101 +/- 12.4 vs 66.8 +/- 12.4 ml min-1; P less than 0.02). Extent of nitrazepam binding to plasma proteins was slightly decreased in obese subjects (% unbound--19.7 +/- 0.4-obese vs 17.9 +/- 0.3%; P less than 0.005). Correction of both Vd (2.62 +/- 0.17-obese vs 2.22 +/- 0.19 l kg-1; NS) and clearance (0.93 +/- 0.06-obese +/- 1.07 +/- 0.07 ml min-1 kg-1; NS) for total body weight (TBW) suggested that increases in obese subjects of both of these parameters were a function of body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Benzodiazepine hypnotic metabolism: drug interactions and clinical implications.

Benzodiazepines are the drugs of choice when initiating hypnotic therapy. Though the mechanism of benzodiazepine action in the central nervous system is similar for all drugs in this class, differences in absorption and pathway of elimination are associated with differences in observed clinical effect. After single-dose administration, onset of hypnotic effect is most closely related to rate of drug absorption and duration of effect is more closely associated with extent of drug distribution. Relative affinity of the individual benzodiazepine for the specific central nervous system binding site may also determine duration of action. During multiple-dose chronic therapy, route of metabolic biotransformation and elimination half-life assume more importance. An increased incidence of adverse drug effects due to high doses of accumulating benzodiazepines may be seen in the elderly and patients with central nervous system deficits or chronic liver disease. Benzodiazepine metabolic biotransformation and clearance is broken into three groups. Group 1--oxidative biotransformation; Group 2--high clearance drugs; Group 3--drug conjugation. Groups 1 and 2 are implicated in a number of drug-disease and drug-drug interactions. Group 3 drugs have little change in patients with liver disease or when administered with inhibitors of drug biotransformation. Clinical implications of these metabolic interactions are variable, but inhibition of Group 1 and 2 benzodiazepine clearance has been associated with increased sedation and psychomotor impairment.

Anti-Anxiety Agents↗
PubMed1986

Steady state verapamil tissue distribution in the dog: differing tissue accumulation.

Plasma, heart, and extracardiac tissue verapamil concentrations were measured after sustained intravenous infusions in 11 dogs to determine the differential tissue accumulation of verapamil. A steady state verapamil concentration of 327 +/- 50 ng/ml decreased the mean arterial blood pressure from 104 +/- 9 to 90 +/- 6 mm Hg (p = 0.08) and the P-R interval increased from 118 +/- 4 to 176 +/- 13 ms (p less than 0.001) with second-degree atrioventricular block developing in 6 animals. Verapamil accumulated in organs in the following order: Lung much greater than kidney greater than spleen greater than ventricular myocardium = liver greater than atrial myocardium greater than cerebral cortex greater than fat = skeletal muscle. Levels in the ventricular free wall were consistently greater than atrial levels, but no difference was observed between left versus right-sided cardiac chambers. In summary, affinity of different organs for verapamil is highly variable and organ-specific; furthermore, differential intracardiac chamber accumulation occurs.

Animals↗
PubMed1986

Verapamil pharmacodynamics and disposition in young and elderly hypertensive patients. Altered electrocardiographic and hypotensive responses.

We studied verapamil pharmacodynamics and disposition in seven young, ten elderly, and seven very elderly hypertensive males. Maximal decrease in mean (+/- SD) blood pressure tended to be greater in the elderly (-13.5 +/- 5.9 mm Hg) and the very elderly patients (-15.9 +/- 9.6 mm Hg) compared with that in young patients (-7.3 +/- 4.2 mm Hg). Disparate effects on heart rate responses were noted with reflex tachycardia in young patients compared with decreases in heart rate among the elderly and very elderly. Sensitivity to verapamil-induced prolongation in electrocardiographic P-R interval was less in the very elderly, and maximal prolongation in P-R interval induced by verapamil was less in the elderly and very elderly. Verapamil disposition was also age related. Total verapamil clearance was decreased in elderly (10.5 +/- 3.5 mL/min X kg; p less than 0.05) and very elderly (8.0 +/- 4.1 mL/min X kg; p less than 0.01) when compared with that in young patients (15.5 +/- 4.5 mL/min X kg). Elimination half-life was prolonged in the elderly (7.4 +/- 3.3 h; p less than 0.01) and very elderly (8.0 +/- 1.2 h; p less than 0.01) compared with that in young patients (3.8 +/- 1.1 h). Our data indicate age- and hypertension-related physiologic changes result in predictable pharmacokinetic changes. However, the complex alterations in verapamil pharmacodynamic responses indicate an interaction between direct drug effects and age- and disease-related changes in hemodynamic and autonomic nervous system function.

Administration, Oral↗
PubMed1986

Paracetamol absorption from a feeding jejunostomy.

Disposition of paracetamol oral elixir was determined in two male patients after administration via feeding jejunostomy and compared with four male controls who received the same dose by mouth. Area under the plasma concentration-time curve, elimination half-life, and time to maximum concentration were similar in both groups after 650 mg paracetamol elixir. The absolute amounts and ratio of paracetamol glucuronide to sulphate, the major urinary metabolites after therapeutic paracetamol doses, were similar after jejunal administration as compared to oral administration. Paracetamol is absorbed and biotransformed in a similar manner after either jejunal or oral administration. Therefore, it may be administered effectively via jejunostomy tube in patients who require this route of administration.

Acetaminophen↗
PubMed1986

Ketoconazole does not impair antipyrine clearance in humans.

The effect of ketoconazole on the kinetics of antipyrine was investigated. The antipyrine Vd showed an overall difference among the 4 trials, but the magnitude of the differences was small. Antipyrine half-life was slightly but not significantly shortened and the antipyrine clearance was essentially identical in the whole study. The data are commented and interpreted.

Adult↗
PubMed1986

Pharmacokinetics and dynamics of (+/-)-verapamil in lean and obese Zucker rats.

To evaluate the mechanism of obesity-induced changes in pharmacokinetics and pharmacodynamics of verapamil observed in humans, single-dose and steady-state kinetic/dynamic studies in obese Zucker rats were done. Seven lean and five obese Zucker rats received a single dose of verapamil (2 mg/kg) and plasma samples were obtained for verapamil concentrations over the following 7 hr. Terminal elimination half-life was significantly prolonged in obese animals compared to lean (mean +/- S.D., 2.68 +/- 0.87 hr obese vs. 1.39 +/- 0.35 hr lean; P less than .01) due to the significantly increased total volume of distribution observed in the obese animals (1.62 +/- 0.28 liters obese vs. 0.83 +/- 0.14 liters lean; P less than .001). There was no significant difference in the total clearance (0.45 +/- 0.16 liters/hr obese vs. 0.43 +/- 0.10 liters/hr lean; NS) between lean and obese animals. A physiological explanation for the increased volume of distribution was evaluated by determining actual distribution of verapamil into tissue during steady-state infusion. Six lean and six obese animals received a loading infusion of verapamil (25 micrograms/min) for 1.2 hr in lean and 1.6 hr in obese rats followed by a constant infusion of 5 micrograms/min for the next 2.5 to 3 hr. Steady-state clearance was similar between groups (0.349 +/- 0.095 liters/hr obese vs. 0.244 +/- 0.066 liters/hr lean; NS). Plasma verapamil concentration at the termination of steady-state infusion was similar between lean and obese rats (0.91 +/- 0.24 microgram/ml obese vs. 1.26 +/- 0.33 microgram/ml lean).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effects of inhalational anesthetics on verapamil pharmacokinetics in dogs.

Six dogs were chronically instrumented in order to collect aortic blood samples and record mean arterial pressure, cardiac output and heart rate. Each animal received verapamil 200 micrograms X kg-1 by 10-min intravenous infusions on four occasions in random sequence: awake, and during halothane 1.2%, enflurane 2.5%, and isoflurane 1.6% anesthesia. Rate of initial distribution of verapamil was reduced during anesthetic exposure. Verapamil intercompartmental clearance from the central compartment to the peripheral compartment was decreased during exposure to halothane and isoflurane, and tended to decrease during enflurane exposure as well. Verapamil terminal volume of distribution at steady-state was reduced by halothane, enflurane, and isoflurane exposure as compared with awake: 65 +/- 10, 80 +/- 9, and 93 +/- 191, respectively, versus 132 +/- 121 (mean +/- SEM; P less than 0.05). Verapamil total clearance was also reduced by halothane, enflurane, and isoflurane as compared with awake: 37 +/- 4, 39 +/- 2 and 41 +/- 31 X h-1, respectively, versus 64 +/- 71 X h-1 (P less than 0.05). Verapamil administered to awake animals resulted in a decrease from baseline in mean arterial pressure; 95 +/- 8 mmHg versus 108 +/- 4 mmHg (P less than 0.05): and an increase in cardiac output; 2.60 +/- 0.33 1 X min-1 versus 1.93 +/- 0.22 1 X min-1 (P less than 0.05). During halothane, enflurane, and isoflurane anesthesia, verapamil administration resulted in a similar decrease in mean arterial pressure; however cardiac output decreased, in contrast to the increase noted in awake animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Inhalation↗
PubMed1986

Doxepin-cimetidine interaction: increased doxepin bioavailability during cimetidine treatment.

The influence of concurrent cimetidine administration on the disposition of doxepin was evaluated in 10 healthy volunteers. Each subject ingested 100 mg of doxepin on two different occasions, once while otherwise drug free and once while receiving cimetidine, 300 mg every 6 hours. Doxepin absorptive parameters--time to peak doxepin plasma concentration (2.3, control, vs. 2.4 hours during cimetidine co-administration) and peak concentration achieved (43.3. vs. 55.5 ng/ml)--were not changed during cimetidine administration. Likewise, doxepin elimination half-life was similar in the control state (12.5 hours) and during cimetidine administration (13.2 hours). However, doxepin area under the plasma concentration-time curve (AUC) was increased during concurrent cimetidine administration (533 vs. 695 ng/ml . hour; p less than 0.05), resulting in a trend toward decreased doxepin oral clearance (4404 vs. 3278 ml/min; 0.05 less than p less than 0.1). Relative bioavailability during concurrent cimetidine treatment was 123% of that during the control trial. Desmethyldoxepin AUC was no different between trials (478, control, vs. 433 ng/ml . hour during cimetidine ingestion). Plasma protein binding of doxepin was similar between trials (percent unbound; 10.5, control, vs. 11.2%) and therefore did not influence calculated AUC. These data indicate that doxepin relative bioavailability is increased during concurrent cimetidine administration and suggest that doxepin hepatic extraction is impaired by cimetidine after oral administration. During chronic doxepin therapy, addition of cimetidine to a therapeutic regimen may result in increased doxepin plasma concentration.

Absorption↗
PubMed1985

Increased cimetidine clearance in burn patients.

To determine the etiology of the decreased efficacy of cimetidine in burned and critically ill surgical patients, we studied the kinetics and dynamics of the drug in eight burned patients at a mean of 12 days after the burn. The kinetics were compared with those of nine healthy controls. The elimination half-life of cimetidine in burned patients was significantly reduced (2.2 v 1.5 hours), and total clearance significantly increased (8.2 v 13.3 mL/min/kg). Creatinine and total cimetidine clearance were highly correlated with size of the burn. In the patients studied, 63% of the dose was excreted in eight hours, compared with 45% after 24 hours in controls. Gastric pH was maintained at 4 or higher as long as plasma levels of cimetidine were held above 0.5 microgram/mL. Thus, the increased clearance of cimetidine might explain the decreased effectiveness of this drug in burned and possibly other surgical patients. Dose schedules may need to be altered to compensate for the enhanced clearance of this drug.

Adult↗
PubMed1985

Phenytoin disposition in obesity. Determination of loading dose.

Fourteen obese subjects (mean body weight, 124 kg; percent of ideal body weight [IBW], 178%) and ten control subjects of normal body habitus (mean body weight, 67 kg; 92% IBW) received 300 mg of phenytoin sodium by ten-minute intravenous infusion. Obese subjects compared with controls had prolonged phenytoin elimination half-life (19.9 v 12.0 hours). Total metabolic clearance of phenytoin was greater in obese than in control groups, although the difference was not significant (59 v 39 mL/min). Phenytoin half-life, inversely proportional to clearance and directly proportional to volume of distribution (Vd), was prolonged in obesity mainly as a result of the increase in Vd in obese subjects (84 v 40 L). Phenytoin loading dose should be calculated on the basis of IBW plus the product of 1.33 times the excess weight over IBW. Very obese individuals will require large absolute loading doses of phenytoin to rapidly achieve therapeutic drug concentrations.

Adult↗
PubMed1985

Ibuprofen disposition in obese individuals.

Eleven obese subjects (weight 114 +/- 11 kg, mean +/- SE) and 11 age-matched subjects with normal body weight (61 +/- 3 kg) were given 600 mg of ibuprofen orally after an overnight fast. Peak ibuprofen concentration was significantly decreased in obese subjects (P less than 0.02), although the time from administration to peak concentration was not different. Ibuprofen volume of distribution was increased in obese subjects, and this increased distribution correlated positively with body weight (r = 0.82; P less than 0.001). Volume of distribution corrected for body weight was decreased in obese subjects, and this decrease correlated negatively with body weight. Ibuprofen clearance was also increased in obese subjects; the increase correlated positively with body weight (r = 0.81; P less than 0.001). Since the independent variables, volume of distribution and clearance, were increased in parallel in the obese subjects, the dependent variable, elimination half-life, was unchanged. Using mean values of distribution calculated from the 2 groups, ibuprofen distribution into body weight in excess of ideal body weight was found to be approximately 0.44 times as extensive as the distribution into ideal body weight. Furthermore, ibuprofen clearance increased in parallel with the volume of distribution and total body weight. Clinically, these data indicate that in obese patients, the ibuprofen dose may be increased without changing the dose interval, in order to achieve necessary plasma concentrations.

Adult↗
PubMed1985

Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives.

The effect of chronic (greater than 3 months) administration of low-dose oestrogen-containing (less than 50 micrograms oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs 1.75 ml/min/kg, respectively) with no change in apparent volume of distribution (0.685 in OCS vs 0.7501/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs 4.09 micrograms/ml) and time to peak concentration after drug administration (1.52 vs 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. This suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users.

Adult↗