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R F Suckow

Publications and source records attributed to R F Suckow.

47 records · Page 3Linked to original sources
PubMed1985

Tricyclic antidepressant and metabolite levels in chronic renal failure.

Serial blood samples were drawn from 12 patients undergoing hemodialysis who were receiving tricyclic antidepressants (TCAs). Samples were drawn before, during, and after a dialysis session (two to 17 sessions per subject). Samples were analyzed by HPLC before and after hydrolysis with beta-glucuronidase/sulfatase to determine the conjugated and nonconjugated metabolites. Analysis of these data in comparison with those of controls with depression and normal renal function showed that: (1) at steady state, tertiary and secondary amine TCA levels did not differ; (2) levels of the hydroxylated metabolites had greater variability and were somewhat higher at steady state; (3) levels of the conjugated hydroxylated compounds were markedly elevated, reaching 500% to 1500% normal; (4) the time to reach a steady-state level appeared to be slightly increased; and (5) elimination t1/2 s of unconjugated and conjugated drug forms were longer in our patients with normal renal function than those reported in the literature. Levels of the tertiary, secondary, and hydroxylated metabolites were not changed by dialysis, whereas there were substantial decrements in glucuronidated metabolite levels. These findings demonstrate increased concentrations of conjugated drug forms and suggest an abnormal distribution or delayed elimination of unconjugated and conjugated metabolites. These observations may shed some light on the apparent hypersensitivity of these patients to TCA side effects, particularly because glucuronides may exert peripheral pharmacologic effects.

Adult↗
PubMed1984

Determination of bupropion and its major basic metabolites in plasma by liquid chromatography with dual-wavelength ultraviolet detection.

A method for the determination of bupropion and its three major basic metabolites in plasma is described. Following an extraction from alkaline plasma into 1.5% v/v isoamyl alcohol in n-heptane, a portion of the acid-backwashed extract was injected onto a column packed with trimethylsilyl reverse-phase material and eluted with a phosphate buffer-acetonitrile (80:20) mobile phase containing an ion-pairing reagent and triethylamine. The compounds were detected with a dual-wavelength UV detector (214 and 254 nm) to optimize sensitivity and facilitate simultaneous detection. The method provides an absolute recovery of approximately 85% for bupropion and approximately 98% for the metabolites. Day-to-day reproducibility did not exceed 4.0% for all compounds. The detection limits were approximately 5 ng/mL for bupropion and 100 ng/mL for the major metabolites. The limit of 100 ng/mL for metabolite quantitation is imposed by the internal standard concentration selected for steady-state studies. In single-dose pharmacokinetic studies, 10% of the steady-state concentration of internal standard was used; this permitted a 10-ng/mL lower limit of detection. Steady-state plasma levels of bupropion and the metabolites from eight different patients are presented.

Bupropion↗
PubMed1984

Determination of trimipramine and metabolites in plasma by liquid chromatography with electrochemical detection.

A procedure for the determination of trimipramine, the demethyl, 2-hydroxy, and 2-hydroxy demethyl metabolites in plasma by liquid chromatography with electrochemical detection is described. A 1-mL plasma sample is made alkaline with a carbonate buffer (pH 9.8) and extracted with 20% ethyl acetate in n-heptane. After back-extraction into an acid phosphate buffer, an aliquot is injected onto a reverse-phase trimethylsilyl-packed column and eluted with a phosphate buffer-acetonitrile mobile phase (65:35) containing n-butylamine. The peaks were detected at +1.1 V versus the silver-silver chloride reference electrode. The method provides absolute recoveries of 60-91% and a day-to-day precision of less than 9% for all compounds. The minimum quantifiable level for all compounds was 3 ng/mL. Steady-state plasma concentration data for 29 depressed patients receiving either 75 mg or 150 mg/d is reported.

Chromatography, High Pressure Liquid↗
PubMed1984

Imipramine and its metabolites: relationship to cerebral catecholamines in rats in vivo.

The relationship between blood and brain levels of imipramine (IMI) and its demethylated and hydroxylated metabolites was studied in rats after chronic administration of IMI. It was found that the combined concentration of IMI and its metabolites was about 10-fold higher in brain than in plasma and this ratio was independent of the dose or the time of sacrifice. However, the brain-to-plasma ratio for the individual compounds varied with the time of sacrifice after the last IMI dose. The metabolite, didesmethylimipramine, was found in significant quantities in plasma and brain tissue with a distribution similar to that of desmethylimipramine. The hydroxylated metabolites constituted less than 6% of the combined concentration of IMI and its metabolites in plasma. Small amounts of 2-OH-desmethylimipramine were found in brain but 2-OH-IMI was rarely detected in cerebral tissue. With the exception of the hypothalamus, there were no significant differences in the distribution of IMI or its metabolites among various brain regions. The relationship between the concentrations of IMI or its active metabolites in plasma or brain and the extracellular availability of cerebral norepinephrine was also studied and found to be nonlinear: the concentration of norepinephrine in the cerebroventricular fluid approached a maximal value when the combined concentration of IMI and its metabolites was 10 micrograms/g in the brain or 1.5 micrograms/ml in plasma. Cerebroventricular application of IMI or each of its metabolites resulted in an increased concentration of both norepinephrine and dopamine in the cerebroventricular fluid whereas the concentrations of catecholamine metabolites remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Simultaneous determination of amitriptyline, nortriptyline and their respective isomeric 10-hydroxy metabolites in plasma by liquid chromatography.

An ion-pair reversed-phase liquid chromatographic method for the determination of the tricyclic antidepressant amitriptyline, the demethylated metabolite nortriptyline, and their respective cis- and trans-hydroxylated metabolites in plasma is presented. After extraction from 1 ml of plasma, the reconstituted residue was chromatographed on a trimethylsilyl packed column using a mobile phase of acetonitrile and acetate buffer with sodium heptane-sulfonate and triethylamine. Recovery of the drugs and its metabolites from plasma ranged from 56 to 99%. The method is suitable for determining plasma concentrations as low as 5 ng/ml (C.V. less than 9%) for all six compounds. Plasma concentrations of amitriptyline and its metabolites from eleven different patients are presented.

Amitriptyline↗
PubMed1982

Determination of mianserin and metabolites in plasma by liquid chromatography with electrochemical detection.

A procedure for the determination of mianserin, desmethylmianserin, and 8-hydroxymianserin in plasma at therapeutic concentrations by liquid chromatography with electrochemical detection is described. Following a multiple-step extraction from alkaline plasma into methyl-tert-butyl ether, the reconstituted extract was injected onto a reversed-phase trimethylsilyl-packed column and eluted with an acetate-acetonitrile mobile phase containing an ion-paired reagent. The method provides an absolute recovery of 71-76% and a day-to-day precision of 5.4-9.1% for each compound at 25 ng/ml. The minimum quantifiable level for all three compounds was 5 ng/ml (RSD greater than 11%), and the detector response was linear up to 500 ng/ml. Fixed-dose steady-state plasma level data for 34 patients are reported.

Biotransformation↗
PubMed1981

Simultaneous determination of imipramine, desipramine, and their 2-hydroxy metabolites in plasma by ion-pair reversed-phase high-performance liquid chromatography with amperometric detection.

An ion-pair reversed-phase high-performance liquid chromatographic (HPLC) method, using an electrochemical detector, is presented for the simultaneous and rapid quantitation of imipramine desipramine, and their 2-hydroxylated metabolites in plasma. The drugs are extracted from 1 ml of plasma at pH 9.7 with ether, back-extracted into 0. M HCl, and reextracted into ether following alkalinization. An efficient electrochemical oxidation reaction at the detector electrode affords a low detection level of approximately 5 ng/ml in a mobile phase of acetonitrile--acetate buffer (40:60) containing 0.005 M heptanesulfonate. Patient data are presented as correlations between the plasma level of each hydroxy metabolite and its respective parent compound. The method is applicable to the laboratory experienced in HPLC.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Enantiomeric determination of the phenylmorpholinol metabolite of bupropion in human plasma using coupled achiral-chiral liquid chromatography.

A coupled achiral-chiral stationary phase liquid chromatographic technique was developed to separate and quantitate the enantiomers of the phenylmorpholinol metabolite (2) of the antidepressant bupropion (1) in human plasma. At the retention time of 2, a switching valve loaded a portion of the eluting compound onto a protein-bonded chiral stationary phase which resolved 2 into the (+) and (-) stereoisomers using an aqueous mobile phase of potassium phosphate (pH = 6.25) and 5% 2-propanol. All eluting compounds were monitored using UV detection at 214 nm, and no plasma endogenous material or other commonly used psychotropic drugs were found to interfere. Within-day and between-day variation were less than 6% over the expected concentration range, and a limit of quantitation of about 125 ng/mL of 2 was observed. Steady-state plasma samples from 17 patients receiving 1 were found to contain the (-) enantiomer to the extent of about 96% of total 2. The potential clinical implications of these results are not known since all previous pharmacological studies were carried out with the racemic 2.

Antidepressive Agents, Second-Generation↗
PubMedDate not supplied

Expression of aspartoacylase activity in cultured rat macroglial cells is limited to oligodendrocytes.

N-acetyl-L-aspartate (NAA) is an important osmolyte in the vertebrate brain and eye, and its cyclical metabolism is accomplished in two separate compartments. In the brain, NAA is synthesized primarily in neurons, and after its regulated release, NAA is hydrolyzed by aspartoacylase, which is present in a glial-associated compartment. However, the precise nature of this hydrolytic compartment has remained obscure. It has been proposed that one role of aspartoacylase in the central nervous system (CNS) is as part of a molecular water pump (MWP) that uses the NAA intercompartmental cycle to remove nerve cell metabolic water against a water gradient and that oligodendrocytes comprise the second compartment in this metabolic sequence. The absence of aspartoacylase activity in Canavan disease (CD), a rare early onset genetic spongiform leukodystrophy, is associated with CNS edema, intramyelinic swelling and a progressive loss of oligdendrocytes. In order to evaluate the MWP hypothesis and its possible relationship to the etiology of CD further, both oligodendrocytes and astrocytes obtained from neonatal rat brain were grown in culture and tested for the presence of aspartoacylase activity. The results of this study show for the first time that aspartoacylase activity is expressed only in oligodendrocytes. The meaning of this observation in understanding the function of the NAA metabolic cycle is discussed.

Amidohydrolases↗
PubMedDate not supplied

Pharmacokinetics of bupropion and metabolites in plasma and brain of rats, mice, and guinea pigs.

Recent reports indicate that bupropion, a novel non-tricyclic antidepressant, is metabolized differently in certain species of animals. To further define the disposition of bupropion, a study was done involving three species, the rat, mouse, and guinea pig, as animal models to evaluate bupropion metabolism. The pharmacokinetic profiles of bupropion and its major basic metabolites, BW 306U and BW A494U, were determined following the ip administration of 40 mg/kg bupropion to these animals. Pharmacokinetic profiles of the parent drug and metabolites from plasma and brain samples were obtained using a liquid chromatographic procedure. Further investigation of the reduced bupropion metabolite BW A494U was carried out by the ip administration of this metabolite to these animals and assaying the plasma and brain samples 90 min after dosing. Analysis of the pharmacokinetic data revealed that the rat quickly metabolized bupropion, but no basic metabolites accumulated. The mouse metabolized bupropion predominantly to BW 306U, whereas the guinea pig converted bupropion to reduced bupropion (BW A494U) as well as BW 306U. Brain/plasma ratios of bupropion among these animals did not vary significantly. However, both metabolites showed dramatic differences in their brain/plasma ratios among these species. When reduced bupropion (BW A494U) was injected, almost 3% of the plasma concentration of BW A494U was determined to be bupropion in the rat. Lesser amounts were converted in the mouse and guinea pig. Therefore, we have demonstrated that distinct differences exist in the metabolism of bupropion in various species of animals. The guinea pig, when compared to the rat or mouse, appears to constitute a model that most closely resembles that of human bupropion metabolism.

Animals↗