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Biomedical subjects

D R Abernethy

Publications and source records attributed to D R Abernethy.

At least 145 records · Page 8Linked to original sources
PubMed1984

Imipramine disposition in users of oral contraceptive steroids.

Ten women on long-term, low-dose estrogen oral contraceptive steroids (OCS) and eight age-matched drug-free female controls received an intravenous infusion of 12.5 mg imipramine. Eleven (six OCS users and five controls) also took a 50-mg oral dose of imipramine on another occasion. After intravenous injection, volume of distribution was much the same in the OCS and control groups and clearance was of the same order (899 and 975 ml/min). Elimination t1/2 was prolonged in OCS users after intravenous doses (17.8 vs 25.5 hr) but did not change after oral doses (18.4 vs 19.1 hr). Imipramine plasma protein binding was of the same order in both groups. Absolute bioavailability increased in OCS users (from 27.1% vs 44.1%), which resulted in a trend toward decreased apparent oral clearance (from 4649 vs 2322 ml/min). Women who used OCS regularly show little change in imipramine kinetics after intravenous dosing. After oral dosing absolute systemic bioavailability increased, resulting in decreased apparent oral clearance in the absence of any change in oral elimination t1/2. Imipramine (with high first-pass hepatic extraction) is nonrestrictively cleared, with drug elimination predominantly a function of hepatic blood flow. These data are consistent with OCS inhibition of hepatic imipramine oxidation with no alteration in hepatic blood flow resulting from chronic OCS use.

Administration, Oral↗
PubMed1984

Ranitidine does not impair oxidative or conjugative metabolism: noninteraction with antipyrine, diazepam, and lorazepam.

Potential interactions of ranitidine with antipyrine, diazepam, and lorazepam were evaluated. Ten healthy male subjects were injected intravenously with antipyrine (1.2 gm), diazepam (10 mg), or lorazepam (2 mg) on two randomly assigned occasions, once in the otherwise drug-free state and once while concurrently taking a therapeutic ranitidine dose of 150 mg every 12 hr. Kinetic analysis for antipyrine showed no change in elimination t1/2 between trials (mean, 11.6 and 11.5 hr) with no change in volume of distribution (Vd) or total clearance (0.77 and 0.75 ml/min/kg). Diazepam analysis also showed unchanged t1/2 (32.3 and 28.9 hr) with no change in Vd or total clearance (0.42 and 0.39 ml/min/kg). Lorazepam as well had unchanged t1/2 (11.7 and 11.3 hr), Vd, and total clearance (1.52 and 1.65 ml/min/kg). Therefore ranitidine, unlike cimetidine, has no effect on either human hepatic drug oxidation, as measured by antipyrine and diazepam clearance, or human drug conjugation, as measured by lorazepam clearance.

Adult↗
PubMed1984

Trimipramine kinetics and absolute bioavailability: use of gas-liquid chromatography with nitrogen-phosphorus detection.

Kinetic parameters were derived from trimipramine and desmethyltrimipramine plasma concentrations after administration of intravenous (12.5 mg) and oral (50 mg) trimipramine in nine subjects. Elimination t1/2 after intravenous dosing was (mean +/- SE) 23 +/- 1.9 hr. Volume of distribution by the area method was 30.9 +/- 3.5 l/kg and total metabolic clearance was 15.9 +/- 1.5 ml/min/kg. Plasma protein binding of trimipramine, as determined by equilibrium dialysis, averaged 94.9%, with a range of 93.8% to 96.4%. Peak plasma level attained was 28.2 +/- 4.4 ng/ml at 3.1 +/- 0.6 hr after oral dosing. Absolute bioavailability was 41.4% +/- 4.4% (range of 17.8% to 62.7%). These data indicate that trimipramine has incomplete and variable systemic availability, that it is more highly protein bound than other tricyclic antidepressants, and, on the basis of its elimination t1/2, that it could be administered on a twice-daily basis without marked interdose fluctuations in plasma levels.

Administration, Oral↗
PubMed1984

Plasma protein binding of drugs after severe burn injury.

Plasma protein binding in seven severely burned (35% to 85% of body) patients 1 to 25 days after burn injury was examined for two drugs: diazepam (DZ), which binds mainly to serum albumin (ALB), and imipramine (IMI), which binds primarily to alpha 1-acid glycoprotein (AAG). Protein binding was determined by equilibrium dialysis, and AAG concentrations were measured by radial immunodiffusion. AAG concentrations increased from 36 to 99 mg/dl (day 1) to 221 to 268 mg/dl (days 5 to 20). The IMI free fraction values decreased from 11.2%-19.7% to 5.5%-7.8% and correlated well with AAG concentrations. IMI free fraction values were lower in burned patients (10.8% +/- 0.8%) than in healthy controls (15.3% +/- 0.7%). In contrast, DZ free fraction did not correlate with AAG or ALB concentrations. The DZ free fraction ranged from 1.5% to 8.04%, and changes in a given individual did not relate to time after injury. Free fraction of DZ was higher in the burned population (3.5% +/- 0.37%) than in healthy controls (1.25% +/- 0.05%). Basic drugs that are highly bound to AAG may show progressive, increased binding after burn injury, whereas drugs binding to ALB may decrease after burn injury. Such binding changes can alter the interpretation of total serum or plasma drug concentrations.

Adolescent↗
PubMed1984

Age effects on alpha-1-acid glycoprotein concentration and imipramine plasma protein binding.

Alpha-1-acid glycoprotein concentration and imipramine binding to plasma proteins were determined in a cohort of 69 subjects, aged 20-97 years. No subject had evidence of acute or chronic inflammatory disease or malignancy, or was receiving tricyclic antidepressant therapy. Alpha-1-acid glycoprotein concentration increased significantly with increasing age (r = 0.28; P less than 0.02). Imipramine percentage not bound to plasma proteins was negatively related to alpha-1-acid glycoprotein concentration (r = -0.30; P less than 0.01); however, there was no relationship between subject age and percentage imipramine unbound. Though alpha-1-acid glycoprotein concentration increases with advancing age, because only a small proportion of the variability is explained by age, with other undefined factors being more important, drugs predominantly bound to alpha-1-acid glycoprotein such as imipramine may not have a clinically or statistically significant change in protein binding with increasing age in the absence of overt clinical illness.

Adult↗
PubMed1984

Plasma levels of trazodone: methodology and applications.

A sensitive (to 5.0 ng/ml) and specific method for analysis of the antidepressant trazodone is described. The method utilizes gas-liquid chromatography with nitrogen-phosphorus detection. Applicability of the method is demonstrated by (1) a pharmacokinetic study in a normal volunteer who received 50 mg trazodone orally and (2) steady-state plasma level determinations of 2 patients receiving trazodone in the treatment of depression.

Administration, Oral↗
PubMed1984

Differential effects of isoniazid and oral contraceptive steroids on antipyrine oxidation and acetaminophen conjugation.

Factors influencing hepatic oxidation of antipyrine and conjugation of acetaminophen were evaluated in volunteers who received 1.0 g of antipyrine intravenously and on a different occasion a 650 mg intravenous dose of acetaminophen. In study one, subjects received both drugs in the control state and at another time during coadministration of isoniazid (INH), 180 mg daily. In control versus INH conditions, mean clearance of antipyrine was reduced from 0.67 to 0.60 ml/min/kg as was clearance of acetaminophen from 4.97 to 4.23 ml/min/kg, but these differences were not statistically significant. In study two, females on low-dose estrogen oral contraceptives (OC) and drug-free controls matched for age received both drugs. Compared to controls, OC users had reduced total clearance of antipyrine (0.71 vs. 0.50 ml/min/kg; p less than 0.005) and prolonged antipyrine t1/2 (9.6 vs. 13.3 h; p less than 0.005). For acetaminophen, however, OC users had higher clearance (5.2 vs. 6.1 ml/min/kg) and shorter t1/2 (2.2 vs. 1.9 h) although differences did not attain statistical significance. Clearance of antipyrine and acetaminophen across both studies was not statistically significantly correlated within individuals (r = 0.22). The capacities for drug oxidation and conjugation appear to be controlled by different mechanisms.

Acetaminophen↗
PubMed1984

Verapamil and norverapamil determination in human plasma by gas-liquid chromatography using nitrogen-phosphorus detection: application to single-dose pharmacokinetic studies.

A sensitive (to 0.5 ng/ml) and specific method for the determination of verapamil and norverapamil which utilizes gas-liquid chromatography with nitrogen-phosphorus detection is described. A basic extraction with acid back-wash and final basic reextraction is used for the preparation of plasma samples. Standard curves using alpha-isopropyl-alpha-[(N-methyl-N-homoveratryl)-beta-aminoethyl]- 3,4- dimethoxyphenylacetonitrile hydrochloride (D-517) are linear for concentrations from 0.5 to 200 ng/ml for both verapamil and norverapamil. Within-day and between-day reproducibility is good with a coefficient of variation less than 10% for all concentrations. Recovery is complete for both verapamil and norverapamil. Application of the method is demonstrated by a pharmacokinetic study in a normal volunteer who received 10 mg verapamil hydrochloride by intravenous infusion.

Adult↗
PubMed1984

Pharmacokinetics, central nervous system uptake, and lipid solubility of propranolol, acebutolol, and sotalol.

The relation of in vitro lipophilicity, based on octanol:buffer partition ratio and on reverse-phase liquid chromatographic retention, to in vivo pharmacokinetics and central nervous system entry was evaluated for the beta-blockers propranolol, acebutolol, and sotalol. Anesthetized cats received single intravenous doses, following which plasma kinetics, cerebrospinal fluid (CSF) kinetics and brain tissue uptake were determined over the next 4 h. Propranolol, by far the most lipophilic beta-blocker in vitro, had the highest in vivo metabolic clearance and volume of distribution (Vd), the most rapid entry into CSF, and the highest brain:plasma uptake ratio (38.0). Sotalol, the most hydrophilic drug in vitro, had the lowest in vivo clearance and Vd, the slowest CSF entry, and the lowest brain:plasma ratio (0.52). Acebutolol had slightly greater in vitro lipophilicity than sotalol, intermediate values of in vivo plasma kinetics and CSF entry rate, and a slightly greater brain:plasma uptake ratio (0.71). Thus, differences among beta-blockers in lipid solubility are associated with predictable differences in plasma kinetics, and rate of entry into CSF. Furthermore, the relative extent of entry into brain is lower for hydrophilic as opposed to lipophilic beta-blockers.

Acebutolol↗
PubMed1984

Benzodiazepine drug-drug interactions commonly occurring in clinical practice.

Pharmacokinetic drug-drug interactions which involve currently available benzodiazepines may be classified into two major categories: interactions which affect benzodiazepine rate of absorption, and interactions which affect clearance and, therefore, elimination half-life. Ethanol is the prototype for absorptive interactions. Concurrent ethanol use and oral ingestion of benzodiazepine derivatives uniformly slows the rate but does not change the extent of benzodiazepine absorption. Interactions which affect benzodiazepine clearance affect only those derivatives which are oxidatively metabolized or cleared as a function of hepatic blood flow (high first-pass clearance). Conjugated benzodiazepines are not implicated in such interactions. Rifampin and chronic ethanol use induce benzodiazepine oxidation, while cimetidine, oral contraceptives, ethanol (acute ingestion), disulfiram, isoniazid, and propranolol inhibit benzodiazepine oxidation. In addition, ethanol, cimetidine and isoniazid decrease first-pass hepatic extraction of triazolam, enhancing its systemic availability and decreasing oral clearance. The pharmacokinetic consequence of induction of benzodiazepine oxidation is higher clearance and decreased steady-state concentrations during chronic dosing. Conversely, inhibition of benzodiazepine oxidation decreases clearance and increases steady-state benzodiazepine concentrations during chronic dosing. Because a correlation of benzodiazepine plasma concentration and pharmacological effect is not established, the pharmacodynamic consequences of these interactions are not currently well characterized.

Anti-Anxiety Agents↗
PubMed1984

Cimetidine disposition in obesity.

Cimetidine pharmacokinetics were studied in 13 otherwise healthy but obese volunteers, having a mean body weight of 113 kg and a mean percentage ideal body weight (IBW) of 179%. Sixteen healthy volunteers of normal body habitus (64 kg, 99% IBW) served as controls. All subjects had normal renal function and no laboratory or clinical evidence of hepatic or cardiac dysfunction. After administration of 200-300 mg of cimetidine by rapid intravenous injection, multiple plasma samples obtained over the next 24 h were analyzed for cimetidine concentration by high pressure liquid chromatography. Elimination half-life was not different between obese and control subjects (2.23 versus 2.08 h). Apparent volume of distribution was also similar between subject groups (120 versus 106), as was total metabolic clearance (616 versus 579 ml/min). Using percentage IBW as a measure of obesity, no relationship was found between percentage IBW and apparent volume of distribution (r = 0.29). Cimetidine similarly distributes into IBW in both obese and normal weight subjects, and there is minimal distribution of cimetidine into excess body weight over IBW. Furthermore, there is no difference in total metabolic clearance or half-life of cimetidine between obese and control subjects. Cimetidine dosage in clinical practice should therefore be calculated on the basis of IBW, which better reflects lean body mass, instead of total body weight, which reflects adipose tissue weight in addition to lean body mass.

Adult↗
PubMed1984

Serum haloperidol concentrations and clinical response in acute psychosis.

Steady state serum haloperidol concentrations measured by gas-liquid chromatography and a neuroleptic radioreceptor assay were compared to clinical response in 21 acutely psychotic inpatients. Serum concentrations measured by the two assay methods correlated well with each other, although the neuroleptic radioreceptor assay was much less sensitive. There was also a significant linear relationship between haloperidol dose (mg/kg/day) and steady state serum concentration. The correlation between haloperidol serum concentrations and clinical response after 2 to 3 weeks was nonlinear and most pronounced in the intermediate range (15 to 40 ng/ml). Further studies will be needed to establish with certainty the existence and exact limits of a therapeutic window.

Adolescent↗
PubMed1984

Imipramine-cimetidine interaction: impairment of clearance and enhanced absolute bioavailability.

Six healthy volunteers each received imipramine on four occasions in random sequence, i.v. (12.5 mg) and p.o. (50 mg) in a drug-free state and i.v. and p.o. while taking cimetidine 300 mg every 6 hr. After i.v. doses, elimination half-life of imipramine was increased during cimetidine treatment (22.1 vs. 15.5 hr, P less than .02) as a result of decreased total metabolic clearance (623 vs. 1048 ml/min, P less than .05) with no change in volume of distribution (17.2 vs. 19.8 liters/kg) or plasma protein binding (unbound percent, 17.7 vs. 16.5%). After single p.o. imipramine doses, peak imipramine blood levels achieved were greater during cimetidine therapy (34.4 vs. 19.3 ng/ml, P less than .05) and area under the time/concentration curve was greatly increased (569 vs. 306 ng/ml X hr, P less than .05). Desipramine, the biologically active metabolite of imipramine, was measurable only after p.o. doses. Desipramine area under the time/concentration curve was increased during cimetidine therapy after p.o. imipramine doses (274 vs. 152 ng/ml X hr, P less than .05), suggesting that desipramine clearance was inhibited as well. Comparison of i.v. and p.o. imipramine doses indicated absolute bioavailability was 40.2% in the control state and increased to 75.3% (P less than .05) during cimetidine treatment. Imipramine, with both impaired total metabolic clearance and enhanced bioavailability, in conjunction with increased accumulation of desipramine, would have marked increases in steady-state plasma concentration of both imipramine and desipramine with concurrent cimetidine therapy during chronic p.o. treatment.

Administration, Oral↗
PubMed1984

Effect of age, gender, and obesity on midazolam kinetics.

The effects of age, sex, and obesity on the kinetics of single intravenous (iv) and oral doses of midazolam were evaluated in healthy volunteers who received 2.5-5 mg of iv midazolam on one occasion and 5-10 mg orally on another. Kinetics were determined from multiple plasma midazolam concentrations measured during 24 h after dosage. Midazolam elimination half-life (t1/2) after iv dosage was significantly prolonged in elderly (aged 60-74 yr) versus young (24-33 yr) males (5.6 vs. 2.1 hours, P less than 0.01) and total clearance was significantly reduced (4.4 vs. 7.8 ml X min-1 X kg-1, P less than 0.01), leading to increased systemic availability of the oral dose (50% vs. 41%, P less than 0.05). However total volume of distribution calculated by the area method (Vd) (1.6 vs. 1.3 1/kg) and protein binding (3.5 vs. 3.4% unbound) did not differ between groups. Among women there were no significant differences between elderly (64-79 yr) and young (23-37 yr) volunteers in t1/2 (4.0 vs. 2.6 h), clearance (7.5 vs. 9.4 ml X min-1 X kg-1), Vd (2.1 vs. 2.0 1/kg), protein binding (3.7% vs. 3.7% unbound), or oral bioavailability (38% vs. 36%). In obese volunteers (mean weight 117 kg; 173% of ideal weight) versus control subjects of normal weight (66 kg, 95% of ideal weight) matched for age, sex, and smoking habits, midazolam Vd was increased significantly (311 vs. 114 1, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1983

Antipyretic analgesic drugs as models for studies of drug disposition in old age.

Alterations in drug metabolizing capacity associated with the aging process can be elucidated using analgesic-antipyretic agents as model compounds. Antipyrine serves to profile drug oxidizing capacity. Drug oxidation is significantly impaired in old age, but age-related changes are far greater in men than in women. Acetaminophen analogously serves to profile conjugating capacity, which is minimally influenced by age both in men and in women. Changes in the capacity to biotransform these model compounds are reasonably well predictive of parallel changes in the same person's ability to metabolize other drugs transformed by the same pathway.

Acetaminophen↗
PubMed1983

Methods for the determination of lorazepam and chlordiazepoxide and metabolites in brain tissue. A comparison with plasma concentrations in the rat.

Rapid and sensitive methods are described for determining lorazepam and for determining chlordiazepoxide and its metabolites in brain tissue of the rat. Lorazepam was determined by means of solvent extraction and electron-capture gas-liquid chromatography and concentrations as low as 5 ng/g tissue could be measured. High-performance liquid chromatography with UV detection was used to determine chlordiazepoxide and its metabolites and was sensitive to 0.1 micrograms/g tissue. The methods were used to investigate the brain and plasma pharmacokinetics of these compounds in animals that had been chronically treated with lorazepam or chlordiazepoxide. In both experiments brain and plasma levels of all compounds assayed were found to correlate highly.

Animals↗