Search PubMed⌕ Search

Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 289 records · Page 16Linked 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

Pharmacokinetic noninteraction of triazolam and ethanol.

Five healthy volunteers received a single 0.5-mg dose of triazolam on two occasions: once with 100 to 200 ml of water, and on a second trial with 60 ml of commercial vodka mixed with 60 ml of water. There were no significant differences between control and ethanol-coadministration trials in peak serum triazolam level (5.4 vs. 5.4 ng/ml), time of peak level (1.5 vs. 1.6 hours), elimination half-life (2.8 vs. 2.6 hours), or apparent oral clearance (6.6 vs. 7.9 ml/min/kg). The potential pharmacodynamic interaction of triazolam and ethanol is more important than the minimal pharmacokinetic interaction.

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

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

Adverse reactions to triazolam, flurazepam, and placebo in controlled clinical trials.

Adverse reactions were evaluated from 45 double-blind controlled clinical trials involving triazolam 0.25 mg (N = 731), triazolam 0.5 mg (N = 2004), flurazepam 30 mg (N = 899), and placebo (N = 1771). Excessive CNS depression was the most frequent adverse effect, reported in 14.2% of trials with triazolam 0.25 mg, 19.5% with triazolam 0.5 mg, 23.9% with flurazepam 30 mg, and 6.4% with placebo. With the exception of orolingual complaints associated with flurazepam, all other categories of adverse reactions were equally or more frequent with placebo than with active medications. Unusual or excessive adverse reactions were not reported.

Adult↗
PubMed1984

Plasma concentrations and clinical effects after single oral doses of prazepam, clorazepate, and diazepam.

In a double-blind parallel-group pharmacokinetic and pharmacodynamic study, 31 healthy volunteers received single oral doses of prazepam (10 mg), clorazepate (7.5 mg), or diazepam (5 mg). Appearance in plasma of diazepam and of desmethyldiazepam was rapid after administration of diazepam and clorazepate, respectively, with peak plasma concentrations reached within an average of 1 hour. After oral prazepam, however, desmethyldiazepam appeared in blood slowly, with the highest mean concentration at 6 hours postdosage. Clinical self-ratings of fatigue and of "feeling spacey" were significantly different among groups, with changes over baseline being more marked with clorazepate and diazepam than with prazepam. Thus, differences in absorption rate of orally administered benzodiazepines can lead to differences in the intensity of single-dose effects, despite administration of doses that are equivalent in terms of long-term anxiolytic efficacy.

Administration, Oral↗
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↗