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Biomedical subjects

C L DeVane

Publications and source records attributed to C L DeVane.

At least 109 records · Page 6Linked to original sources
PubMed1985

Pharmacokinetics of bupropion and its major basic metabolites in normal subjects after a single dose.

The pharmacokinetics of bupropion (BUP) and its three major basic metabolites (the erythroamino alcohol [EB], the threoamino alcohol [TB], and the hydroxy [HB] metabolites) were characterized after a single, oral, 200 mg dose of BUP in six healthy men. Twenty-one sequential plasma samples for analysis by HPLC were drawn from each subject over the 56-hour period after dosing. Pharmacokinetic analyses were by noncompartmental methods. The mean elimination t1/2 values of BUP, TB, EB, and HB were 9.8, 19.8, 26.8, and 22.2 hours, respectively. The mean plasma AUCs of TB and HB were 2.4 and 10.3 times greater, respectively, than that for BUP. Because of the substantial presence of these metabolites in systemic circulation, further studies are recommended to understand further their roles in the clinical profile of this new antidepressant.

Adult↗
PubMed1985

Stability of bupropion and its major metabolites in human plasma.

Bupropion (BUP) is a new, monocyclic, second-generation antidepressant with efficacy comparable with that of the tricyclics but possessing a more favorable side-effect profile. Therapeutic drug monitoring services are expected to be widely available following the marketing of BUP, yet relatively little has been published on its clinical pharmacokinetics. The purpose of this study was to assess the drug's plasma stability and to determine the best storage conditions for conducting pharmacokinetic studies of BUP and its major metabolites. Human plasma was spiked with known concentrations of BUP and its major basic metabolites, threo-amino alcohol (TB), erythro-amino alcohol (EB), and hydroxy metabolite (HB), and incubated under varying conditions of temperature and pH. BUP showed a log linear degradation that was both temperature and pH dependent. BUP half-life in pH 7.4 plasma stored at 22 and 37 degrees C was 54.2 and 11.4 h, respectively. Incubation at 37 degrees C, pH 2.5 to 10, for 48 h had minimal effect on metabolite concentrations. These results indicate that drug degradation must be considered in studies involving the incubation of plasma for protein binding determinations and the collection and storage of plasma samples for drug concentration analysis during therapeutic drug monitoring.

Antidepressive Agents↗
PubMed1985

Buspirone: a new type of anxiolytic.

Buspirone is a member of a new class of agents known as azaspirodecanediones, and represents the first nonbenzodiazepine anxiolytic to be introduced in the U.S. in recent years. It does not resemble the benzodiazepines or older anxiolytics such as meprobamate and the barbiturates in pharmacologic profile. Buspirone lacks anticonvulsant activity, interacts minimally with central nervous system depressants such as alcohol, and does not cause muscle relaxation. The drug is reported to have minimal sedating effect, to cause no impairment of driving-related skills, and to have no euphoriant effect or addictive potential. With this low side-effect profile, buspirone should not require Drug Enforcement Agency scheduling controls. Clinical trials indicate buspirone is efficacious in the treatment of mild to moderate anxiety disorders. Answers to questions of possible side effects related to dopaminergic intractions must await post-marketing experience. Buspirone is a suitable addition to drug formularies as its pre-marketing data suggest several advantages compared with anxiolytics currently available.

Animals↗
PubMed1984

Cerebral and blood pharmacokinetics of imipramine and its active metabolites in the pregnant rat.

A single IP dose of imipramine (IMI) was administered to pregnant rats. Whole blood, plasma, and brain concentrations of IMI, desipramine (DMI), and their 2-hydroxylated metabolites were separated by high-pressure liquid chromatography and quantified by fluorescence detection. IMI and DMI rapidly appeared in brain tissue in concentrations greatly exceeding those in whole blood and plasma. The much higher concentration and longer persistence of DMI in brain compared to IMI suggests that the predominant central effects from administered IMI result from biotransformation to DMI. The metabolite: "parent" area under the curve ratios for the hydroxylated metabolites indicate that their contribution to the pharmacologic effects of IMI and DMI are probably negligible.

Animals↗
PubMed1984

The analysis and disposition of imipramine and its active metabolites in man.

Single oral and intramuscular (i.m.) doses of imipramine (IMI) were administered to four normal males. Serum and urine concentrations of IMI, desipramine (DMI) and their unconjugated 2-hydroxy metabolites were measured by high-pressure liquid chromatography (HPLC). Urinary conjugated 2-hydroxy metabolites were also measured after enzyme hydrolysis. Computer analysis of serum concentration and urinary excretion rate data allowed confirmation of drug and metabolite kinetics, and calculation of pharmacokinetic parameters. The rapid appearance of the metabolites in serum indicates that sequential first-pass metabolism of IMI involves both hydroxylation and demethylation. However, the dose-normalized areas under the serum concentration-time curves indicate that the fractions of the doses converted to metabolites were similar after both routes of IMI administration. Similar total fractions of the i.m. and oral doses recovered in urine indicate complete absorption of the oral doses. Inclusion of the metabolites increased the apparent availability of active components after oral IMI from 22%-50% to 45%-94%. Both the 2-hydroxy metabolites exhibited formation rate-limited kinetics, whereas DMI kinetics were elimination rate-limited. The t1/2 of IMI and 2-hydroxyimipramine (2-OH-IMI) was 6-18 h, while that of DMI and 2- hydroxydesipramine (2-OH-DMI) was 12-36 h. The t1/2 of these compounds was 1.5-2 times longer after the i.m. doses. The metabolite/parent ratios and the disposition of the individual metabolites confirm findings that chronic dosing results in only limited accumulation of hydroxy metabolites.

Administration, Oral↗
PubMed1984

Quantification of imipramine and its major metabolites in whole blood, brain, and other tissues of the rat by liquid chromatography.

An assay procedure is presented using high-performance liquid chromatography and fluorescence detection for simultaneous determination of imipramine, desipramine, and their 2-hydroxylated metabolites in whole blood and various tissues of the rat. By modifying methods previously described for plasma, we have developed an assay method for sensitive, reproducible quantitation of these compounds in rat plasma, whole blood, brain, liver, and fetus. Increasing the volume of the extraction solvent (20% butanol in hexane) increased recovery of imipramine and desipramine to greater than 90% for all tissues examined. No interfering peaks were observed for any of the tissues studied. Addition of n-butylamine as a modifier to the mobile phase decreased the retention of all four compounds and decreased peak tailing of the demethylated compounds. The total elution time was less than 15 min. Using these methods the coefficient of variation for all four compounds was generally less than 5% for each of the five tissues examined. The calibration curves were linear for standard concentrations of 25-2,000 ng/ml spiked tissue homogenate. This method has sufficient sensitivity and specificity for use in pharmacokinetic studies of imipramine.

Animals↗
PubMed1984

Mechanism and management of important psychotherapeutic drug interactions.

Interactions between drugs can result in unintended changes in desired pharmacologic effects. Because psychotherapeutic drugs represent the most widely used class of pharmacologic agents, physicians must anticipate possible consequences of their interactions. An overview of drug interaction reports reveals that they can be usefully divided into those with either a pharmacokinetic or pharmacodynamic mechanism. We review the most important of these interactions and present methods to avoid or minimize their untoward effects.

Anticoagulants↗
PubMed1984

The neuroleptic malignant syndrome: presentation and treatment.

The neuroleptic malignant syndrome is a potentially lethal reaction following the use of antipsychotic medications. The four cardinal signs are hyperthermia, muscular rigidity, autonomic dysfunction, and altered consciousness. The differential diagnosis of the syndrome includes malignant hyperthermia of anesthesia, heat stroke, and acute lethal catatonia. Treatment consists of prompt recognition of the syndrome and initiation of intense supportive measures to manage the hyperthermia and prevent secondary complications. Clinical reports describing beneficial results from use of anticholinergic agents, amantadine, bromocriptine, and dantrolene are reviewed.

Anesthesia↗
PubMed1984

Concentrations of imipramine and its metabolites during enuresis therapy.

Plasma concentrations of imipramine and three of its metabolites were determined in children 6 to 15 years of age who received imipramine for treatment of nocturnal enuresis. In 14 patients with reliable data the reduction in wet nights after beginning drug therapy had no apparent relationship to either imipramine concentration alone or imipramine combined with its metabolites. This finding may be related to the relatively low drug concentrations in this group of patients, a high placebo response rate, or noncompliance with the prescribed dosage regimen. Determining plasma imipramine concentrations during treatment for enuresis has questionable value as an aid to improve clinical response. This practice may occasionally be justified when avoidance of toxicity is a major concern.

Adolescent↗
PubMed1982

Hemoperfusion for imipramine overdose: elimination of active metabolites.

The serum concentrations of imipramine and its pharmacologically active metabolites were followed during resin hemoperfusion for imipramine overdose. The initial serum concentration of 2-hydroxy-imipramine plus 2-hydroxy-desipramine was 13.3% of the total tricyclic antidepressant level (imipramine + desipramine + hydroxymetabolites). Despite high extraction ratio (greater than or equal to 0.75) and clearances (130--180 mL/min) for both imipramine and its metabolites, the calculated amount of drug removed was small. Only 0.91% of the estimated dose ingested was removed as imipramine, 0.52% as desipramine, and 0.33% as hydroxylated metabolites. While the hydroxylated metabolites of imipramine may contribute to its toxicity, it is unlikely that the small amount removed can explain reports of apparent clinical benefit from hemoperfusion.

Adult↗
PubMed1982

Toxic hepatitis and single daily dosage imipramine therapy.

Liver function abnormalities have occasionally been associated with imipramine since the drug was introduced in 1957. The mechanism by which the drug produces hepatotoxicity has not been determined but may involve a direct toxic effect or a hypersensitivity reaction. In this case, a patient receiving 6 mg/kg (300 mg) of imipramine daily developed elevated liver enzymes while the plasma imipramine concentration was found to be in a therapeutic range. This case suggests that single daily dosing of tricyclic antidepressants may be more hazardous to the liver than divided doses.

Adult↗
PubMed1981

Desipramine and 2-hydroxy-desipramine pharmacokinetics in normal volunteers.

Disposition characteristics of desipramine and its metabolite, 2-hydroxy-desipramine, were determined in four healthy male volunteers following an oral 50 mg dose of desipramine. Nonlinear least-squares regression of concentration-time data indicated that parent drug disposition could be described by a one-compartment open pharmacokinetic model for two subjects and by a two-compartment model for two subjects. The early appearance of 2-hydroxy-desipramine and its high peak concentrations indicates that desipramine probably undergoes pre-systemic elimination partly through formation of 2-hydroxy-desipramine. The substantial production of 2-hydroxy-desipramine, as reflected by the area under its concentration-time curve which was 51% to 94% of that for desipramine, indicates that accumulation will occur following multiple dosing. As 2-hydroxy-desipramine may possess antidepressant activity, future studies designed to assess the therapeutic effect of desipramine should account for the presence of its pharmacologically active metabolite.

Adult↗
PubMed1981

Plasma concentration monitoring of hydroxylated metabolites of imipramine and desipramine.

Steady-state serum concentrations of imipramine (IMI), its demethylated metabolite desipramine (DMI), and the active, hydroxylated metabolites, 2-hydroxy-imipramine (2-OH-IMI) and 2-hydroxy-desipramine (2-OH-DMI) were monitored in 126 psychiatric patients receiving IMI therapy. DMI and 2-OH-DMI concentrations were determined in a similar group of 61 DMI-treated patients. Although significant correlations exist between hydroxy metabolite and precursor concentrations, considerable variability was also found. Mean (+/- SD) ratios for the IMI patients were: 2-OH-IMI:IMI = 0.27 (+/- 0.19) and 2-OH-DMI:DMI = 0.56 (+/- 0.30). The ratio of DMI:IMI for males and 2-OH-DMI:DMI for females decreased with age (r = -0.42 and -0.32, respectively, p less than 0.01). Variable metabolite concentrations and the uncertainty of their relative psychoactivity may contribute to the difficulties in relating antidepressant efficacy to serum concentrations of the administered IMI or DMI.

Adolescent↗