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Biomedical subjects

M Divoll

Publications and source records attributed to M Divoll.

At least 19 recordsLinked to original sources
PubMed1984

Noninteraction of temazepam and cimetidine.

The possible kinetic interaction of the hypnotic temazepam and the H2-receptor antagonist cimetidine was evaluated. Nine healthy male and female volunteers received a 30-mg oral dose of temazepam on two occasions in random sequence, separated by at least 1 week. On one occasion, temazepam was given in the otherwise drug-free state; on the other, temazepam was given with concurrent administration of cimetidine, 300 mg every 6 h. Mean pharmacokinetic parameters for temazepam in control versus cimetidine trials were: peak plasma concentration, 560 versus 498 ng/mL; time of peak concentration, 2.0 versus 2.1 h after the dose; volume of distribution, 1.30 versus 1.39 L/kg; elimination half-life, 9.9 versus 11.4 h; total clearance, 1.59 versus 1.60 mL/min/kg; free fraction of temazepam in plasma, 4.1 versus 3.8% unbound. Cimetidine has been shown to reduce the metabolic clearance of the benzodiazepines that are biotransformed by oxidative mechanisms. Temazepam, transformed by conjugation, appears unaffected by the coadministration of cimetidine.

Adult↗
PubMed1984

Absolute bioavailability of imipramine: influence of food.

Imipramine hydrochloride (IMI) was administered to 12 healthy volunteers on three occasions in random sequence: 12.5 mg IV, 50 mg orally after overnight fast, and 50 mg orally 30 min after eating a standardized breakfast. IMI concentrations were measured by gas-liquid chromatography using nitrogen-phosphorous detection and pharmacokinetic and bioavailability parameters determined by iterative nonlinear least-squares regression analysis. After IV administration, mean kinetic variables were: volume of distribution, 21.0 l/kg; total clearance, 12.8 ml/min per kg, and elimination half-life, 21. h. Mean absolute bioavailability of IMI in the fasting state was 43.6%. When IMI was administered immediately after the standardized meal, absolute bioavailability was 44.1%. After oral administration, the time to peak IMI level was not changed by concurrent food ingestion (2.8 vs 3.2 h after dosage), and the peak IMI concentration was no different (35 vs 30 ng/ml). Thus concurrent food ingestion has no effect on IMI absolute bioavailability, peak concentration attained after oral dosage, or the time to peak concentration.

Administration, Oral↗
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

Propranolol kinetics: use of automated liquid chromatography.

Concentrations of propranolol in plasma or cerebrospinal fluid can be reliably quantitated using liquid chromatography with fluorescence detection. After addition of pronethalol as internal standard, alkalinized samples are extracted with hexane:isoamyl alcohol (98:2); the organic extract is separated, evaporated to dryness, reconstituted in mobile phase (acetonitrile:water:acetic acid, 30:69:1), and chromatographed on a reverse-phase C-18 column. Effluent is monitored with fluorescence detection at excitation and emission wavelengths of 235 and 335 nm. The simplified extraction procedure plus an automatic injection system allows one person to analyze up to 100 samples per day. Sensitivity limits are .5 ng of propranolol per ml of sample, and the method is applicable to experimental and clinical pharmacokinetic studies.

Adult↗
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

Alprazolam kinetics in the elderly. Relation to antipyrine disposition.

The pharmacokinetics of alprazolam, a triazolobenzodiazepine anxiolytic-antidepressant, were assessed in 32 healthy men and women aged 21 to 78 years after a single 1.0-mg oral dose. Peak alprazolam levels averaged 20.4 ng/mL and were reached a mean of 1.25 hours after dosage. Mean elimination half-life did not differ significantly between elderly and young women, nor did total metabolic clearance. However, half-life was significantly prolonged, and total clearance significantly reduced, in elderly v young men. Antipyrine oxidizing capacity was also evaluated, and half-life for the two drugs was highly correlated, as were their metabolic clearances. Thus, old age is associated with impaired capacity to oxidize alprazolam, but this effect is far more apparent in men than in women. A test of antipyrine half-life and clearance may help identify slow or rapid metabolizers of alprazolam.

Adult↗
PubMed1983

Absolute and relative bioavailability of oral acetaminophen preparations.

Eighteen healthy volunteers received single 650-mg doses of acetaminophen by 5-min intravenous infusion, in tablet form by mouth in the fasting state, and in elixir form orally in the fasting state in a three-way crossover study. An additional eight subjects received two 325-mg tablets from two commercial vendors in a randomized crossover fashion. Concentrations of acetaminophen in multiple plasma samples collected during the 12-hr period after each dose were determined by high-performance liquid chromatography. Following a lag time averaging 3-4 min, absorption of oral acetaminophen was first order, with apparent absorption half-life values averaging 8.4 (elixir) and 11.4 (tablet) min. The mean time-to-peak concentration was significantly longer after tablet (0.75 hr) than after elixir (0.48 hr) administration. Peak plasma concentrations and elimination half-lives were similar following both preparations. Absolute systemic availability of the elixir (87%) was significantly greater than for the tablets (79%). Two commercially available tablet formulations did not differ significantly in peak plasma concentrations, time-to-peak, or total area under the plasma concentration curve and therefore were judged to be bioequivalent.

Acetaminophen↗
PubMed1983

Interaction of cimetidine with the triazolobenzodiazepines alprazolam and triazolam.

The influence of cimetidine on the pharmacokinetics of alprazolam and triazolam, two triazolobenzodiazepines metabolized by hepatic microsomal oxidation, was evaluated in a series of healthy volunteers. Subjects ingested single 1.0 mg dose of alprazolam or 0.5 mg doses of triazolam on two occasions, with and without concurrent administration of cimetidine (300 mg) every 6 h. For alprazolam, which has a low hepatic clearance and low extraction ratio, cimetidine significantly impaired total metabolic clearance (1.05 versus 1.66 ml/min/kg, P less than 0.005), resulting in significantly prolonged elimination half-life (16.6 versus 12.4 h, P less than 0.005). For triazolam, which has higher hepatic clearance and an intermediate extraction ratio, total clearance was reduced by cimetidine (3.9 versus 5.9 ml/min/kg), causing a significant increase in total area under the plasma concentration curve (25 versus 38 ng/ml X h, P less than 0.02). However, elimination half-life of triazolam was not influenced by cimetidine (3.3 versus 3.2 h), indicating that the reduction in clearance was manifested as increased systemic availability. Thus, cimetidine impairs the clearance of both alprazolam and triazolam, but the consequences of the kinetic change are different because of the differing hepatic extraction profiles of the two drugs.

Adult↗
PubMed1983

Close correlation of acetaminophen clearance with that of conjugated benzodiazepines but not oxidized benzodiazepines.

The clearance of the antipyretic-analgesic drug acetaminophen, biotransformed in humans by glucuronide and sulfate conjugation, was evaluated in 32 healthy young and elderly volunteers. Subjects received a single 650-mg dose of acetaminophen, and multiple plasma concentrations measured over the next 12 h. Random subgroups of subjects also participated in studies of the oxidized benzodiazepines diazepam, desmethyldiazepam and alprazolam, and of the conjugated benzodiazepines lorazepam, oxazepam and temazepam. Acetaminophen clearance was not related to that of the oxidized benzodiazepines, but was highly correlated with clearance of lorazepam (r = 0.70, n = 11, p less than 0.02), oxazepam (r = 0.76, n = 14, p less than 0.005) and temazepam (r = 0.63, n = 16, p less than 0.01). Thus acetaminophen may serve as a probe or marker compound to evaluate drug conjugating capacity in humans.

Acetaminophen↗
PubMed1983

Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives.

Women on low-dose estrogen oral contraceptives (OC) and drug-free control women matched for age, weight, and cigarette smoking habits, received single 2-mg IV doses of lorazepam or single 30-mg oral doses of oxazepam, two benzodiazepines metabolized by glucuronide conjugation. Kinetics were determined from multiple plasma concentrations measured during 48 hr after dosing. Mean kinetic variables for lorazepam in control and OC groups (n = 15 in each group) were: volume of distribution (Vd), 1.33 and 1.45 l/kg; elimination t1/2, 13.1 and 12.2 hr; total clearance, 1.25 and 1.50 ml/min/kg; free fraction in plasma, 10.3% and 10.3% unbound. For oxazepam, kinetic variables in the two groups (n = 14 and 17) were: Vd, 1.05 and 1.19 l/kg; t1/2, 7.6 and 7.2 hr; total clearance, 1.60 and 2.03 ml/min/kg; free fraction, 4.6% and 4.9% unbound. None of these differences were significant. Thus, metabolic clearance by glucuronidation of lorazepam and oxazepam is not significantly affected by OC, in contrast with the highly significant reduction in clearance of the oxidized benzodiazepine diazepam.

Adult↗
PubMed1983

Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity.

Thirty-three healthy male and female volunteers aged 21 to 87 years received a single 0.5 mg oral dose of triazolam. Plasma triazolam concentrations were measured in multiple samples drawn during 24 h after the dose. Mean triazolam elimination half-life was not significantly different between young and elderly men (3.0 vs 4.6 h), nor between young and elderly women (2.7 vs 3.2 h). However, apparent oral clearance of triazolam was significantly reduced in elderly as compared to young groups of both sexes, leading to higher peak plasma concentrations and increased total area under the curve. Values of half-life and clearance of antipyrine, a low-extraction hepatically oxidized compound, were poorly correlated with those of triazolam (r = 0.34 and 0.44, respectively), suggesting different mechanisms controlling age-related changes in clearance of these two hepatically oxidized drugs.

Adult↗
PubMed1983

Pharmacokinetics of benzodiazepine hypnotics.

Three benzodiazepine derivatives are currently indicated specifically for the treatment of insomnia in the United States. Flurazepam is biotransformed to at least two rapidly appearing and rapidly eliminated intermediate metabolites which probably contribute to sleep induction. The final metabolite, desalkylflurazepam, appears slowly, but has a long half-life ranging from 40 to 150 h. This metabolite accumulates extensively during multiple dosage. Temazepam is a slowly absorbed drug and has an intermediate half-life in the range of 10-20 h. Triazolam has an intermediate absorption rate, but is rapidly eliminated (half-life 1.5-5 h) making it essentially non-accumulating. Understanding of the pharmacokinetics of benzodiazepine hypnotics can contribute to understanding of their clinical properties.

Anti-Anxiety Agents↗
PubMed1983

Diazepam versus lorazepam: relationship of drug distribution to duration of clinical action.

Eight healthy volunteers received single intravenous doses of diazepam and lorazepam on two separate occasions. Kinetic parameters of drug distribution and clearance were determined by measurement of multiple plasma concentrations following each dose. Elimination half-life for diazepam averaged 51.2 hr, as compared with 15.7 hr for lorazepam. However, after correction for individual differences in protein binding (mean free fraction 1.5% for diazepam versus 10.1% for lorazepam), the volume of distribution of unbound diazepam (mean 133 liter/kg) was more than 10 times larger than that of lorazepam (mean 12 liter/kg). This is consistent with in vivo measurements of lipid solubility indicating that diazepam has a much larger octanol/water partition coefficient than lorazepam. Thus, the shorter duration of action of a single intravenous dose of diazepam as compared with lorazepam, despite the much longer half-life of diazepam, is explained by the more extensive tissue distribution of unbound diazepam.

Adult↗
PubMed1983

Pharmacokinetic properties of benzodiazepine hypnotics.

The kinetic properties of three benzodiazepine hypnotics are reviewed. Flurazepam serves as a precursor for at least two rapidly appearing and rapidly cleared metabolites that may contribute to sleep induction and are nonaccumulating. The final metabolite of flurazepam (N-desalkylflurazepam), however, has a long half-life and accumulates during repeated dosage. Temazepam has a relatively slow rate of absorption and an intermediate half-life in the range of 10 to 20 hours. Triazolam has an intermediate rate of absorption; due to its ultrashort half-life (1.5 to 5 hours), triazolam is a non-accumulating hypnotic. Taken together with sleep laboratory studies and clinical trials, knowledge of the kinetic profile of benzodiazepine hypnotics can assist in evaluating their clinical benefits and disadvantages.

Absorption↗
PubMed1983

Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen.

The influence of obesity on the distribution or clearance of lorazepam and oxazepam, two benzodiazepines biotransformed by glucuronide conjugation, was studied in a series of obese subjects (mean weight 113 kg; mean percent IBW 179%) and healthy controls of normal body habitus matched for age and sex. Overweight subjects and controls received 2 to 3 mg of lorazepam intravenously or 30 mg of oxazepam orally. Absolute Vd in obese compared to control subjects was increased for both lorazepam (131 vs. 77 L, p less than 0.001) and oxazepam (97 vs. 38 L, p less than 0.001). When normalized to body weight, Vd/kg was similar for both drugs. Total metabolic clearance was similarly increased in the obese cohort for lorazepam (102 vs. 63 ml/min, p less than 0.005) and oxazepam (157 vs. 50 ml/min, p less than 0.001). Again, when normalized to body weight, clearance per kilogram was similar for both drugs. Since both Vd and clearance increased with body weight, elimination half-life (dependent on both Vd and clearance) was not significantly different in obese subjects (lorazepam 16.5 vs. 14.9 hr; oxazepam 7.7 vs. 8.9 hr). A random subgroup of obese and control subjects received a single intravenous dose of acetaminophen, also biotransformed by conjugation. Acetaminophen clearance was significantly correlated with that of lorazepam (r = 0.59, p less than 0.01) and oxazepam (r = 0.87, p less than 0.001), and clearance of LRZ and OXZ were similarly intercorrelated (r = 0.72, p less than 0.01). Thus obesity is associated with enhanced capacity for biotransformation of drugs via glucuronide conjugation. conjugating capacity increases in proportion to TBW and is consistent among drugs biotransformed by this mechanism.

Acetaminophen↗
PubMed1983

Pharmacokinetics of alprazolam.

The metabolic profile and human pharmacokinetics of alprazolam, a benzodiazepine of unique chemical structure, are discussed. Alprazolam's pharmacokinetics may be altered by age and sex, body weight, and concurrent treatment with cimetidine. The unique structure of alprazolam may be associated with a wider range of biologic activity than is seen with other benzodiazepines.

Age Factors↗