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Biomedical subjects

B Mellström

Publications and source records attributed to B Mellström.

At least 55 records · Page 3Linked to original sources
PubMed1984

Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes.

The 2-hydroxylation of desmethylimipramine (DMI) and the 4-hydroxylation of debrisoquine (D) were studied in healthy subjects and in human liver microsomes. A single oral dose of DMI (25 mg) was given to 18 healthy subjects previously phenotyped with D (13 rapid and five slow hydroxylators). Urine was collected for 24 hr and DMI and total 2-hydroxydesmethylimipramine (2-OH-DMI) levels were determined by HPLC. The urinary ratio DMI/2-OH-DMI correlated strongly (r = 0.92) with the urinary ratio of D to 4-hydroxydebrisoquine (D/4-OH-D). The two hydroxylations were also studied in human liver microsomes from 10 different subjects. Formation rates of the hydroxylated metabolites correlated strongly (r = 0.869). Moreover, D competitively inhibited the 2-hydroxylation of DMI. These findings suggest that both are hydroxylated by the same cytochrome P-450 isozyme.

Adult↗
PubMed1983

Correlation between nortriptyline and debrisoquine hydroxylation in the human liver.

The benzylic hydroxylation of nortriptyline (NT) and debrisoquine (D) by isolated human liver microsomes from eight subjects was studied. There was a strong correlation between the 10-hydroxylation of NT and the 4-hydroxylation of D (r = 0.96). The ability to hydroxylate D was also measured in vivo as the ratio between D and 4-OH-D in urine after oral administration of the drug to four subjects. This estimate of hydroxylation capacity agreed with the in vitro measurements. Liver microsomes from a subject defined as a poor in vivo oxidizer of D hydroxylated NT and D unusually slowly. Separation of microsomal proteins by SDS-gel electrophoresis indicated a relative lack of a cytochrome P-450 isozyme with a molecular weight of 54,500 in the liver from the poor oxidizer.

Adult↗
PubMed1983

Amitriptyline metabolism: relationship to polymorphic debrisoquine hydroxylation.

Amitriptyline AT demethylation to nortriptyline NT was determined in nine healthy subjects who had been phenotyped with respect to debrisoquine D hydroxylation capacity. AT demethylation was calculated from the ratio between the plasma AUCs of NT after single oral doses of AT and NT. Plasma clearance of AT by demethylation did not correlate with the ratio between D and 4-hydroxy-D in urine (rs = -0.55).

Adult↗
PubMed1982

Nortriptyline formation after single oral and intramuscular doses of amitriptyline.

Oral (50 mg) and intramuscular (25 mg) amitriptyline (AT) was given to six normal subjects and the area under the plasma concentration-time curve (AUC) for nortriptyline (NT) formed was calculated. There was no difference between the AUCs (corrected for dose) after the two routes of administration. The ratio between the AUCs (corrected for dose) after the two routes of administration. The ratio between AUCoral and AUCim averaged 0.95 (range 0.69 to 1.13). After intramuscular AT maximum NT plasma concentration was reached after 24 to 48 hr, whereas it was 8 to 24 after oral dosing.

Administration, Oral↗
PubMed1981

E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation.

Eight healthy subjects [who were phenotyped with a debrisoquine (D) hydroxylation test] were selected to cover a wide range in the ratio between D and 4-hydroxydebrisoquine (4-OH-D) in the urine. After a single oral dose of nortriptyline (NT) the metabolic clearance by 10-hydroxylation in the E-position, but not in the Z-position, correlated closely to the metabolic ratio D/4-OH-D (rs = -0.88, p less than 0.01). This indicates that common enzymatic mechanisms are involved in the hydroxylation of D and the E- but not the Z-10-hydroxylation of NT. Slow hydroxylators of NT and D excreted less 10-hydroxynortriptyline in urine and had lower plasma clearance of NT than the rapid hydroxylators. The strong correlation (r = 0.96) between the total plasma clearance of NT and the metabolic clearance by E-10-hydroxylation shows that this metabolic reaction is important in the disposition of the drug.

Debrisoquin↗
PubMed1980

Clomipramine treatment of obsessive-compulsive disorder. II. Biochemical aspects.

Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid, and the noradrenaline metabolite 4-hydroxy-3-methoxyphenyl glycol were measured in CSF before and after three weeks' treatment of severe obsessive-compulsive disorder with clomipramine hydrochloride. Patients who responded to clomipramine treatment had significantly higher CSF levels of 5-HIAA before treatment. The amelioration of obsessive-compulsive symptoms was positively correlated to the reduction of CSF concentrations of 5-HIAA during clomipramine treatment but negatively correlated to plasma concentrations of clomipramine. Reduction of CSF concentrations of 5-HIAA, which probably reflects drug action on central serotonin neurons, was maximal at a plasma clomipramine concentration of about 300 nmole/L. At higher levels, the reduction of CSF levels of 5-HIAA was smaller. The antiobsessive effect of clomipramine may be connected to its capacity to inhibit serotonin uptake.

Adult↗
PubMed1980

Interindividual differences in amitriptyline demethylation.

Amitriptyline (AT) and its demethyl metabolite nortriptyline (NT) were given orally and intramuscularly to 6 normal subjects, and the areas under the blood concentration--time curves (AUC) were calculated. The mean unbound fraction of AT and NT in plasma was 5.4% and 8.3%, respectively. The blood-plasma ratio of NT was nearly double that of AT, which was close to unity. The mean systemic availability of oral relative to intramuscular AT and NT was 43% and 61%. The calculated mean oral blood clearance of AT as measured by dose (oral)/AUC was 1.6 1/min. The demethylation of orally administered AT varied considerably between the 6 individuals (from 25% to 89%) and correlated with oral drug clearance. Demethylation was estimated from the AUC applied to the NT metabolite. The estimated oral clearance of AT from demethylation ranged from 0.21 to 1.80 1/min.

Administration, Oral↗
PubMed1979

Intraindividual similarity in the metabolism of amitriptyline and chlorimipramine in depressed patients.

The two structurally similar tricyclic antidepressant drugs amitriptyline (AT) and chlorimipramine (CI) were administered to 15 patients in a cross-over study. Approximately equimolar daily doses of the two drugs (5 mumol/kg body weight) were given as commercial tablets. Steady state plasma levels of the parent drugs and the demethyl metabolites were determined by high performance liquid chromatography. An about 5-fold interindividual variation was found in plasma levels of all four compounds. As the reciprocal plasma level during multiple dosing is proportional to the clearance of a compound, this parameter was used for linear regression analysis. In the 15 patients there was a significant correlation between the reciprocal plasma levels of CI and its metabolite demethylchlorimipramine (r = 0.76; p less than 0.001) and also between AT and its metabolite nortriptyline (r = 0.52; p less than 0.05). The reciprocal plasma levels of the parent compounds AT and CI were closely correlated (r = 0.87; p less than 0.001). A similar correlation was found for the demethyl metabolites (r = 0.77; p less than 0.001). The results indicate that similar factors control the plasma levels of AT and CI during treatment and that similar enzymes may be involved in the metabolism of the two drugs.

Amitriptyline↗
PubMed1978

Ion-pair liquid chromatography of amitriptyline and metabolites in plasma.

A method is described for the determination of amitriptyline and nortriptyline in the plasma of patients during treatment. The method is based on liquid chromatography of the amines as ion-pairs with perchlorate. The separation column is packed with silica gel, and a mixture of diisopropyl ether, dichloromethane, methanol and water containing the counter ion is used as eluent. High efficacy and stability of the system is achieved. The separation of metabolites is demonstrated. The cis- and trans-10-hydroxy isomers of amitriptyline and nortriptyline are easily resolved with this chromatographic system.

Amitriptyline↗
PubMed1977

Ion-pair liquid chromatography of steady-state plasma levels of chlorimipramine and demethylchlorimipramine.

A method for the determination of chlorimipramine and its metabolite demethylchlorimipramine in the plasma of depressed patients during treatment is described. The method involves extraction of the parent drug, its metabolite and the internal standard from plasma, back-extraction into an acidic aqueous phase and re-extraction into a small volume of organic phase. Separation and quantitation are carried out by ion-pair partition chromatography with UV detection. Accurate determination if possible down to levels of 30 and 60 nmole per liter of plasma for chlorimipramine and the metabolite, respectively, when 1 ml of plasma is used. The coefficient of variation is 7.3% or less at different levels for chlorimipramine and demethylchlorimipramine. Plasma levels of the parent drug and the metabolite measured by this liquid chromatographic method and by a gas chromatographic procedure with electron-capture detection were in good agreement (r = 0.98). The steady-state plasma level of the metabolite was always higher than that of the parent drug in the 34 depressed patients investigated. The mean ratio between the metabolite and the parent drug was 2.7 +/- 1.1 (S.D.) Large inter-individual differences in the levels of the two compounds in patients receiving similar doses were found.

Chromatography, Ion Exchange↗