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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.

Amine metabolites and cortisol were measured in four consecutive 3 ml samples of lumbar cerebrospinal fluid (CSF). There were pronounced concentration gradients for both 5-hydroxyindoleacetic acid and homovanillic acid, and there was no difference in the gradients of 11 controls and 17 psychiatric patients (10 depressed). As there was a close correlation between the mean of the first two fractions and the mean of all four fractions, a concentration obtained in 6 ml can be used to calculate that in a 12 ml CSF sample. In psychiatric patients there was a slight, but statistically significant concentration gradient for 3-methoxy-4-hydroxyphenylglycol (unconjugated as well as conjugated). No gradient was found for cortisol in CSF.

Thirty-five imipramine treated patients were phenotyped with regard to polymorphic drug oxidation using sparteine and/or debrisoquine. During treatment with 100 mg imipramine per day the mean steady-state concentrations and ratios in 28 extensive metabolizers were: imipramine 169 nmol/l; desipramine 212 nmol/l; 2-OH-imipramine/imipramine 0.25; 2-OH-desipramine/desipramine 0.57. The corresponding values in two poor metabolizers were: imipramine 455 and 302 nmol/l; desipramine 1148 and 1721 nmol/l; 2-OH-imipramine/imipramine 0.06 and 0.05; 2-OH-desipramine/desipramine: 0.09 and 0.04 respectively. The metabolic ratios (MR) sparteine/dehydrosparteine and debrisoquine/4-OH-debrisoquine (% of dose in 12-h urine samples) correlated poorly with the imipramine steady-state concentrations during administration of 100 mg per day, but quite well with the desipramine steady-state concentrations. Significant negative correlations were found between sparteine and debrisoquine MR and the 2-OH-imipramine/imipramine and 2-OH-desipramine/desipramine ratios. In most patients the initial dose was changed to obtain concentrations in the therapeutic range, and concentrations for imipramine + desipramine of (mean +/- SD) 713 +/- 132 nmol/l were achieved in 33 patients. The therapeutic dose was 50 mg per day in one poor metabolizer and ranged from 50-400 mg per day in 32 extensive metabolizers. There was a weak negative correlation between sparteine MR and daily dose. Treatment with imipramine inhibited metabolism of both sparteine and debrisoquine (MR values about doubled), but did not affect the interpatient correlations.

Autoinduction of carbamazepine (CBZ) metabolism was investigated in 3 children (10 to 13 yr old) using tetradeuterium-labeled CBZ (CBZ-D4). Prior to treatment, CBZ and CBZ-D4 given as a mixture had almost identical kinetics in each patient. During maintenance therapy with CBZ, part of the CBZ was exchanged for CBZ-D4 on 3 occasions. The clearance of CBZ-D4 given on the second day of therapy was 0.036 ± 0.003 1 · kg−1 · hr−1, whereas it had been 0.028 ± 0.003 before treatment. After 17 to 32 days of treatment, clearance doubled (0.056 ± 0.010) but during the next 4 mo there was no further increase, indicating that the autoinduction was complete within 1 mo. As a corollary there was a decrease in steady-state plasma levels. Clinical Pharmacology and Therapeutics (1980) 27, 83–88; doi:10.1038/clpt.1980.13

– Repeated lumbar punctures in 16 healthy volunteers showed reproducible concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF). In seven depressed patients, studied during two or three illness periods, the metabolite concentrations were also fairly stable. In 11 patients CSF concentrations of 5-HIAA, but not of HVA, were higher after recovery than during depression. This increase of 5-HIAA after recovery was confined to patients whose initial serotonin metabolite levels were low. The finding constitutes further evidence of a biochemical heterogeneity within the depressive disorders, and suggests that patients whose CSF 5-HIAA is low during a depressive episode may have a less stable serotonin system than other patients with depressive illness.

Nine inpatients with a major depressive disorder were treated with the novel selective MAO-A inhibitor amiflamine at a dose of 2.5 mg b.i.d. for 3 weeks in an open study. Two patients who improved during this time continued with the same dose for another 3 weeks. (During a later depressive episode one of these patients was shown to be a placebo responder.) Six patients who did not respond during the first period were then given 5 mg b.i.d. for 3 weeks. One of these patients improved on this increased dosage. The most frequent adverse symptoms were difficulty in sleeping and headache. There was a pronounced variation in the plasma and cerebrospinal fluid (CSF) levels of the parent drug and mono-and didemethylmetabolites. One patient with extremely high levels of the parent drug (slow demethylator of amiflamine) was a slow hydroxylator of debrisoquine. Two other patients were rapid metabolizers of both drugs. There was no consistent effect on the levels of the amine metabolites 5-HIAA, HVA or HMPG in CSF du...

Conjugation of racemic E-10-hydroxynortriptyline (E-10-OH-NT) with glucuronic acid was studied in the liver microsomal fraction of rats and humans. The diastereomeric glucuronides of E-10-OH-NT were resolved and quantitated by HPLC. Only the (+)-enantiomer was glucuronidated in liver microsomes from humans. Rat liver microsomes catalyzed the formation of both glucuronides. Phenobarbital pretreatment of rats increased the glucuronidation of both enantiomers about five-fold. The formation rate of (+)-E-10-OH-NT glucuronide varied from 5.5 to 33.2 pmol/mg x min, in microsomes from 13 humans. High activity was found in individuals previously treated with pentobarbital. Inhibition experiments with human liver microsomes showed that amitriptyline is a potent competitive inhibitor of (+)-E-10-OH-NT glucuronidation. p-Nitrophenol, paracetamol and 2-hydroxydesipramine also inhibited this reaction.

Platelet monoamine oxidase (MAO) activity and cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), and 4-hydroxy-3-methoxyphenylglycol (HMPG) were simultaneously measured in 20 currently depressed patients, 11 recovered depressed patients, 15 nondepressed suicide attempters, and 42 healthy control subjects. Both 5HIAA and HVA were positively and significantly correlated to platelet MAO activity in the healthy subjects, but not in any of the patient groups. Suicide attempters had significantly lower CSF 5HIAA than nonsuicidal patients.

30 patients with different diagnosis, mainly acute schizophrenic patients, were treated with Haloperidol in different doses ranging from 2–40 mg a/day. 10 patients with acute schizophrenia were treated with a fix dose (16 mg). Blood samples for assay of plasma Haloperiodol levels were collected once a week and after 4 weeks the ameliorations were evaluated.The inter-individual variation in plasma levels at the same dose was high. The therapeutic response, in agreement with earlier studies, indicated that a concentration of Haliperidol of about 10 ng/ml could be adequate in the treatment of acute psychotic schizophrenia.

The active and major metabolite of nortriptyline (NT), E-10-hydroxynortriptyline (E-10-OH-NT), was taken orally as the hydrogen maleate in single doses by nine healthy subjects. The doses (10 to 100 mg) were completely absorbed, as shown by the high urinary recovery of 86.1% ± 9.9%. Of the given dose, 51.2% ± 8.7% was recovered as conjugated E-10-OH-NT and 23.9% ± 4.3% was recovered as unchanged compound. The plasma t1/2 of E-10-OH-NT was 8.0 ± 1.2 hours and total plasma clearance was 47.5 ± 10.3 L/hr. The rate of elimination varied little between individuals. There was no indication of dose-dependent elimination. The mean apparent volume of distribution was 7.7 ± 2.1 L/kg. Single oral doses of 50 mg E-10-OH-NT significantly increased the plasma levels of norepinephrine in both the supine and standing positions (P < 0.01). Pulse rate increased in the standing but not the supine position. These effects might result from inhibition of neuronal uptake of norepinephrine by E-10-OH-NT. Coupled with its low affinity for muscarinic receptors, these kinetic and pharmacodynamic features of E-10-OH-NT call for further phase I studies. Clinical Pharmacology and Therapeutics (1986) 40, 261–267; doi:10.1038/clpt.1986.173

The relative affinities of nortriptyline (NT) and its 10-hydroxymetabolites to rat brain muscarinic acetylcholine receptors have been determined by competition with 3 H-quinuclidinyl benzilate binding. It is shown that the major NT metabolite, E-10-OH-NT, has only 1 18 the affinity of NT for the muscarinic receptor. Since this metabolite is equipotent to NT in inhibiting neuronal noradrenaline uptake, it is suggested that it might be of clinical value as an antidepressant by virtue of having less anticholinergic side-effects than NT itself.

The novel drug zimelidine 50--300 mg/day was administered to 12 depressed patients. After about 3 weeks plasma levels of the demethyl metabolite, norzimelidine, were almost thrice those of the parent drug. During incubation of slices of rat brain cortex in plasma from the treated patients, the neuronal uptake of serotonin and noradrenaline was 51.7 +/- 10.2 and 82.8 +/- 9.6%, respectively, of the control values. The uptake inhibition both of serotonin and noradrenaline was correlated with the plasma level of norzimelidine (r = 0.62 and 0.63, respectively). The major central metabolites of serotonin (5-HIAA) and noradrenaline (HMPG) in cerebrospinal fluid (CSF) decreased significantly (29 and 11%, respectively) during treatment with zimelidine. Although there was no mean change in the major dopamine metabolite (HVA) in CSF, the level during treatment (as percentage of the pretreatment level) was correlated with the effect of 5-HIAA in CSF. Thus, administration of zimelidine caused a relatively selective inhibition of serotonin uptake, mainly due to norzimelidine. A small but significant inhibition of noradrenaline uptake was also seen, but this effect was less pronounced than during chlorimipramine treatment. There was an effect on the dopaminergic system, probably secondary to the action of serotonergic neurons.

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.

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 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 hr after oral dosing. Clinical Pharmacology and Therapeutics (1982) 32, 664–667; doi:10.1038/clpt.1982.219

Eight healthy volunteers with a broad range in their ability to hydroxylate debrisoquine, a metabolic reaction which is under polymorphic genetic control, were given single oral doses of nortriptyline and antipyrine. There was a close correlation between an individual's ability to hydroxylate debrisoquine and nortriptyline (measured as plasma clerance of the drug) (Spearman rs = 0.83; p = 0.01). This indicates that these two benzylic hydroxylations are controlled by similar if not identical genetic factors. In contrast to nortriptyline the clearance of antipyrine (assessed in saliva) was not positively related to the ability to hydroxylate debrisoquine.

Theophylline plasma clearance (Clp) and clearance to its metabolites (Clm), as well as antipyrine saliva clearance (Clsal) and its Clm were compared in a crossover study in 25 healthy subjects. They were selected with regard to smoking status (nine smokers, 16 nonsmokers) and oxidation phenotype of debrisoquine and sparteine (six poor metabolizers [PMs] and 19 extensive metaboUzers [EMs]). Clm of theophylline (1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine) correlated (r ≥ 0.92) to each other and to total theophylline Clp (r ≥ 0.97). Smokers had higher Clm to all metabolites, particularly by the N-demethylation pathways. After correction for the effect of smoking, there was no difference between EMs and PMs with regard to theophylline Clp or Clm. Antipyrine clearances by EMs and PMs (Clsal and Clm of 4-OH-antipyrine, 3-OH-methylantipyrine, or norantipyrine) also did not differ. Antipyrine Clsal and Clm correlated to theophylline Clp (r between 0.50 and 0.69). It is concluded that theophylline metabolism (N-demethylations and C-oxidation) is not under the same genetic control as sparteine and debrisoquine oxidations, and that there may be a partial overlap in factors that regulate the metabolism of theophylline and antipyrine. Clinical Pharmacology and Therapeutics (1984) 35, 815–821; doi:10.1038/clpt.1984.118

Carbamazepine and its epoxide in plasma were measured by liquid chromatography in 25 patients treated with a mean dose of carbamazepine of 12.5 +/- 3.3 mg/kg body weight. The mean concentrations of parent drug and metabolite were 5.4 +/- 2.5 mug/ml and 1.10 +/- 0.42 mug/ml, respectively. A singificant correlation was found between the plasma concentrations of the two compounds (r = 0.64; p less than 0.001), but marked interindividual variation existed in the ratio of carbamazepine to carbamazepine to epoxide. Based on simultaneous measurements in plasma and cerebrospinal fluid, the unbound fraction of carbamazepine in plasma was of the order of 20% as compared to 45% for the epoxide. Thirteen ambulant patients suffering from partial epilepsy with complex symptomatology, who were already being treated with phenytoin in optimal doses (plasma level 14-20 mug/ml) were also given carbamazepine. At plasma levels of the latter of about 5 mug/ml there was no further reduction in the frequency of partial or generalized epileptic seizures. In five patients the dose was increased to produce plasma concentrations of 7 - 8 mug/ml. There was still no improvement and side-effects were seen in three patients.

The neurotransmitter metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenyl glycol (HMPG) in cerebrospinal fluid (CSF) were measured by mass fragmentography in 83 patients with melancholia (diagnosed by the Newcastle Inventory and the Research Diagnostic Criteria), and 66 healthy volunteer controls. After adjustment by analysis of covariance for differences between the subject groups in body height, age and sex distribution, significantly (P less than 0.001) lower concentrations of 5-HIAA and HVA were found in the melancholia patients than in the controls. HMPG did not differ between the groups. The differences could not be accounted for by differences in timing or examination techniques, and not by previously administered drugs (all patients were drug-free at the examination, but a minority had taken small amounts of psychotropic drugs prior to the wash-out period). The differences persisted after excluding the suicidal patients. There were no clear-cut differences between unipolar and bipolar patients. It is suggested that the reduced concentrations of 5-HIAA and HVA in the melancholic patients may be due to altered serotonin and/or dopamine functions in the central nervous system, which may be connected with an increased vulnerability to certain types of affective illness.

– Clinical and biochemical effects of two selective 5-HT uptake inhibitors, zimeldine and alaproclate, were studied in 24 hospitalized patients with endogenous depression. According to a randomized parallel group design 14 patients were treated with zimeldine and 10 with alaproclate. The dosage of both zimeldine and alaproclale was 200 mg daily. For the evaluation of the clinical effect, Montgomery & Asberg Depression Rating Scale (MADRS) was used. Seven of 14 patients treated with zimeldine and seven of 10 treated with alaproclate improved. 5-HT uptake inhibition in patients’ platelets and concentration of amine metabolities (5-HIAA, HVA, HMPG) in CSF were studied before and during treatment. After 3 weeks of treatment with zimeldine 5-HIAA and HMPG in CSF decreased significantly while HVA in CSF increased significantly. Zimeldine produced a significant 5-HT uptake inhibition in platelets. During treatment with alaproclate no significant change in amine metabolites concentration in CSF was found and there were no mean changes on 5-HT uptake inhibition in platelets.

Plasma concentrations of nortriptyline (NT) and its major metabolite 10-hydroxy-NT (10-OH-NT) were measured in 30 patients with depression, treated with NT for 3 weeks. Nine patients who recovered completely had plasma concentrations of NT and 10-OH-NT ranging from 358 to 728 nmol/L and from 428 to 688 nmol/L, respectively. Of the 21 patients who did not recover completely, only four had plasma concentrations within the window limited by these two plasma concentration ranges. A correlation was found between the degree of amelioration and the plasma concentration of NT (rs = 0.469; P less than 0.01). Lumbar punctures were performed in 26 patients before and after 3 weeks of NT treatment. During treatment there was a 30.9% mean decrease in the noradrenaline metabolite 4-hydroxy-3-methoxyphenylglycol (HMPG) in cerebrospinal fluid (CSF). We could not evaluate the extent to which this decrease was caused by NT or 10-OH-NT, respectively, because both are strong inhibitors of noradrenaline uptake. The ratio between the concentration of NT and 10-OH-NT in CSF correlated to the reduction of HMPG in CSF (r = 0.397; P less than 0.05) and to the amelioration of depression (rs = 0.623; P less than 0.001). This might indicate that NT and 10-OH-NT interact on the noradrenaline system in a nonadditive way. During treatment there was a 15.2% decrease in CSF concentration of the serotonin metabolite 5-hydroxyindoleacetic acid. The reduction was significantly correlated to the CSF concentration of NT but not to that of 10-OH-NT. This is in accordance with the fact that NT is a more potent inhibitor of serotonin uptake than is 10-OH-NT. The dopamine metabolite homovanillic acid in CSF decreased significantly by 10.0%. The biochemical data indicate that noradrenergic, serotoninergic, and dopaminergic systems are affected by NT treatment and that 10-OH-NT might be more selective on noradrenergic neurons than the parent drug.

In 20 depressed patients treated with nortriptyline (NT) there was a significant relationship between the plasma concentration of NT and the debrisoquine metabolic ratio (rs = 0.77; P less than 0.01). (The debrisoquine test was performed after stopping NT treatment). This is in agreement with the hypothesis that the hydroxylations of NT and debrisoquine are mediated by similar enzymatic mechanisms. In contrast there was no significant relationship between the debrisoquine metabolic ratio and the plasma concentrations of the active metabolite 10-hydroxy-nortriptyline. In 11 of the patients the debrisoquine metabolic ratio was significantly higher during than after NT treatment. This may be due to an inhibition of the debrisoquine hydroxylation by NT.

Carbamazepine-(CBZ)-10,11-epoxide (CBZ-E) was found to decompose in gastric juice in vitro. An antacid did not affect the bioavailability of single CBZ doses given to three subjects and was therefore used to neutralize gastric juice when administering CBZ-E. CBZ-E was given orally as a suspension in two single doses ranging from 10 to 200 mg to each of four healthy subjects. Plasma concentrations of CBZ and CBZ-E were determined with high-performance liquid chromatography. Plasma concentrations and urinary excretion of the end metabolite trans-10,11-dihydroxy-10,11-dihydro-CBZ (trans-CBZ-diol) were measured by mass fragmentography. After dosing with CBZ-E, peak plasma concentrations of the parent compound were reached within 2 hr. Urinary recovery of trans-CBZ-diol was 90 +/- 11% (mean +/- SD) of the dose, indicating almost complete absorption. Plasma kinetics of the epoxide fitted an open one-compartment model with elimination half-lifes (t 1/2s) of 6.1 +/- 0.9 hr. Clearance was 89 +/- 25 ml x kg-1 x hr-1. The urinary excretion t 1/2 of the trans-CBZ-diol was 12.4 +/- 0.9 hr, which is longer (P less than 0.001) than the epoxide plasma t 1/2. There was no indication of dose-dependent kinetics of the epoxide. After 200 mg CBZ to the same subjects, plasma CBZ t 1/2 was 26.0 +/- 4.6 hr and clearance was 23.4 +/- 4.6 ml x kg -1 x hr -1. Of the CBZ dose, 20.5 +/- 2.9% was excreted as the trans-CBZ-diol, which gives an estimate of the percentage of CBZ that is metabolized by the epoxide-diol pathway in healthy subjects. These observations provide a basis for the administration of CBZ-E in patients to assess its clinical effects.

The kinetics of an enteric-coated formulation of carbamazepine-10,11-epoxide (CBZ-E) were studied in healthy subjects. A single oral dose of 100 mg of CBZ-E was given to eight subjects. Four of them were also given a single oral dose of 200 mg of CBZ-E. Plasma concentrations of CBZ-E and urinary excretion of the end metabolite trans-10,11-dihydroxy-10,11-dihydrocarbamazepine (trans-CBZ-diol) were determined by high performance liquid chromatography. Plasma kinetics of CBZ-E fitted an open one-compartment model with plasma elimination half-life of 7.4 \pm 1.8 h (mean \pm SD). The clearance was 105 \pm 17 ml/kg/h and the apparent volume of distribution 1.1 \pm 0.2 L/kg assuming complete bioavailability. There was no indication of dose-dependent elimination of CBZ-E. The recovery of trans-CBZ-diol in urine collected for 3 days was 67 \pm 9% of the given dose. This enteric-coated formulation may thus in the future be used for the evaluation of the clinical effects of CBZ-E in patients. The effects of valpromide on amitriptyline (AMT) and nortriptyline (NT) plasma levels were examined in 20 depressed inpatients. They all were treated with AMT, 125 mg once daily, and 10 patients also received 600 mg of valpromide daily after 10 days on AMT. In the 10 patients receiving valpromide in addition to AMT, the mean AMT level increased from 70.5 \pm 35 to 105.5 \pm 49 ng/ml (p

Benzodiazepines influence on a number of neurotransmitters such as acetylcholine, catecholamines, serotonin, glycine and gamma-aminobutyric acid (GABA), but during recent years the major interest has been focused on the inhibitory transmitter GABA. This paper reviews the hypothesis that benzodiazepines act via GABA-ergic mechanisms in the central nervous system. At NIMH in Washington D.C. a novel method to measure the turnover rate of GABA in rat brain nuclei has been developed (Bertilsson et al., J. Pharmacol. Exp. Therap. 200: 277, 1977). The incorporation of 13C from glucose into glutamic acid and GABA was quantitated in stereomicroscopically isolated nuclei. Using this technique it was shown that the GABA agonist muscimol and diazepam have a similar action. Both drugs decreased the turnover rate of GABA in N. caudatus and accumbens, but not in globus pallidus (Mao et al., Biol. Psychiatry 12: 395, 1977). This gives further support to the theory that diazepam acts as a GABA-mimetic drug.

Carbamazepine (2.7-3 mg/kg) was administered orally as an alcoholic solution (50% v/v) to eight healthy volunteers. Two of the subjects were also given 50 mg and 100 mg of carbamazepine in alcoholic solution and 200 mg as a tablet. Plasma concentrations, which were analysed by mass fragmentography, reached a maximum 1-7 hours after dosing, and then declined monoexponentially with half-lives ranging from 24 to 46 hours. The half-lives were independent of dose. The apparent distribution volume ranged from 0.79 to 1.40 1/kg. It was found that 72% of carbamazepine was bound to plasma proteins with little interindividual variation, and this was not influenced by the presence of diphenylhydantoin or phenobarbital in therapeutic concentrations. The pharmacokinetic parameters calculated from single oral doses were used to predict the steady-state plasma concentration expected after treatment with multiple doses of 200 mg three times daily. The predicted steady-state concentration was 2-3 times higher than that reported in patients undergoing chronic treatment with carbamazepine at this dose level, i.e. the pharmacokinetics of carbamazepine apparently change during multiple dosing.

(1972). Studier av indolaminmetaboliter i cerebrospinalvatska vid depressionssjukdomar. Nordisk Psykiatrisk Tidsskrift: Vol. 26, No. 6, pp. 351-357.

Thecis andtrans isomers of 10-hydroxynortriptyline (10-OH-NT), the major metabolite of nortriptyline (NT) in man, have been separated and quantitated in urine from 6 healthy volunteers who received NT orally, 0.4 mg/kg body weight, three times daily. The isomers were separated by preparative thin layer chromatography and quantitatively determined by gas chromatography as the 10,11-dehydronortriptyline heptafluorobutyryl derivative. The structure of these derivatives producedin vitro was confirmed by gas chromatography — mass spectrometry. Less than 1% of totally excreted 10-OH-NT was accounted for as 10,11-dehydronortriptyline. — Despite interindividual differences in the mean steady-state plasma concentration of NT, the ratio between the two isomers was constant in all subjects (1:4–5). The isomers were both optically active and circular dichroism spectra showed that the asymmetric carbon atoms in the two compounds have different configurations. — It is concluded that NT undergoes stereospecific hydroxylation in man and that there is no correlation between the mean steady-state plasma concentration of NT and the proportion of thecis andtrans isomers formed.

Debrisoquine and S-mephenytoin hydroxylation phenotyping tests were performed in 9 patients before and during treatment with diazepam at a daily dose of 10 or 15 mg. There was no change in either the debrisoquine/4-hydroxydebrisoquine ratio or the ratio of S/R mephenytoin in urine. The hydroxylation of these two test drugs is apparently not inhibited by administration of therapeutic doses of diazepam.

Six hypertensive patients were treated with prazosin up to a final dose of 3-4.5 mg/day. There was a significant reduction of blood pressure. The cerebrospinal fluid (CSF) concentrations of the major metabolites of noradrenaline, dopamine and serotonin were unchanged. This indicates that the antihypertensive effect is not mediated via central monoaminergic neurons as suggested by animal studies.

Seven male patients (age 55–75 years) were debrisoquine‐tested immediately before and after one week of treatment with quinidine sulphate (200 mg x 3‐4 day‐1). Before quinidine all patients were classified as extensive metabolizers (metabolic ratio 0.1‐3.6). During quinidine the formation of 4‐OH‐debrisoquine was practically abolished and the phenotype of the patients was altered to PM (metabolic ratio 15‐51). This is probably due to an inhibition of debrisoquine hydroxylation by quinidine. Inhibition of 4‐OH‐debrisoquine formation was associated with a disproportionate increase in debrisoquine excretion.

Eleven healthy nonsmokers with wide variation in the ability to hydroxylate debrisoquin (D) were given single oral doses of amitriptyline and nortriptyline on different occasions. The urinary D/4-hydroxy-D ratio correlated significantly (P < 0.01) with all three parameters of amitryptyline disposition measured (total plasma clearance, clearance by demethylation, and clearance by pathways other than demethylation), with rs= − 0.89, − 0.78, and − 0.83, respectively. In contrast, we failed to demonstrate such correlations in a previous sample of smokers. Our data suggest that there may be a common regulation of the hydroxylation of D and the oxidative metabolism of amitriptyline in nonsmokers. It is hypothesized that an additional demethylase/hydroxylase is induced in smokers that is not involved in D hydroxylation. Clinical Pharmacology and Therapeutics (1986) 39, 369–371; doi:10.1038/clpt.1986.56

Two subjects from each of the three groups of homozygous rapid, heterozygous, and homozygous non-metabolizers (N-oxidation) of sparteine received a single oral dose of debrisoquine. The urinary ratio of debrisoquine/4-hydroxy-debrisoquine, reflecting the individual's capacity to C-hydroxylate debrisoquine, was closely related to his phenotype for sparteine metabolism. This indicates that the two metabolic reactions are controlled by similar if not identical genetic factors.

Seven patients with trigeminal neuralgia were treated with carbamazepine at three dose levels, each period lasting for six days. A single-blind technique was used, the patients being unaware of the dose changes. During the last three days of each dose treatment, the pain score was determined by the patients and the plasma concentrations of carbamazepine and its epoxide metabolite were measured. There was a correlation between the dose and plasma level of carbamazepine (r = .56; P.01). At the carbamazepine doses studied (200 to 1,400 mg/day), no indication of saturation kinetics was seen. As the ratio between the plasma levels of the epoxide and carbamazepine was relatively low and constant, it was not possible to evaluate the potency of the epoxide. In six of the patients studied a plasma level-effect relationship was found. The best effect was seen at carbamazepine levels between 24 and 43 mu mole/L (5.7 and 10.1 microgram/mL). In one patient who was studied twice, the plasma level-response curve was different on the two occasions. Side effects were recorded in two patients, both with carbamazepine plasma levels above 33 mu mole/L (7.9 microgram/mL).

Carbamazepine (Tegretol) was administered orally to four patients as a single dose, and one week later three times daily for 15-21 days. The plasma half-lives of the drug were shorter in all patients after multiple doses (20.9 +/- 5.0 hours) than after the initial single dose (35.6 +/- 15.3 hours). During the multiple dose the plasma concentrations of the metabolite carbamazepine-10,11-epoxide followed those of the parent drug. The steady-state plasma concentrations expected during multiple doses were calculated from the pharmacokinetic parameters obtained in the single dose studies. The calculated levels were higher (17.2+/-7.2 mug/ml) than the observed maximal concentrations (8.4+/-1.6 mug/ml on day 4), which were obtained 3-4 days after starting the multiple doses. The levels tended to decrease further during the experimental period. The results suggest that carbamazepine induces its own metabolism in man.

Mephenytoin (100 mg) and debrisoquin (10 mg) were administered orally, both separately and together, to 41 healthy subjects. The ratios between the S and R enantiomers of mephenytoin and between debrisoquin and 4-OH-debrisoquin in urine were determined by use of GC. These ratios were used as measures of drug hydroxylation. There was no change in the phenotypic trait values of the two drugs when they were coadministered. Mephenytoin and debrisoquin then were coadministered to 253 healthy Swedish subjects, before bedtime, and urine samples were collected at periods of 0 to 8, 8 to 24, and 24 to 32 hours after drug administration. In the first sample, seven of the 253 subjects (2.8%, 95% confidence interval 0.8% to 4.8%) had an S/R ratio of greater than 0.8; this indicated that they were poor hydroxylators of S-mephenytoin. In the two consecutive samples, the S/R ratios of mephenytoin did not change in these seven persons, whereas it decreased to less than 0.2 in the third sample in the extensive hydroxylators. As was reported before, there was no relationship between the mephenytoin S/R ratio and the debrisoquin metabolic ratio (rs = 0.01). Coadministration of debrisoquin and mephenytoin before bedtime and urine collection during two consecutive nights allow for an accurate determination of both phenotypes in the population. Clinical Pharmacology and Therapeutics (1989) 45, 495–499; doi:10.1038/clpt.1989.63

Six healthy male subjects were randomly given nortriptyline (NT) (25 and 50 mg) and placebo in a double-blind, crossover study. An NT dose of 50 mg (but not 25 mg) clearly reduced saliva flow (P less than 0.05) and was therefore used for comparison with the major and active metabolite of NT, E-10-hydroxynortriptyline (E-10-OH-NT). Equimolar doses of both compounds (and placebo) were randomly given to eight healthy male subjects in another double-blind, crossover study aimed to assess the reduction of saliva flow. NT significantly depressed saliva flow compared with both placebo (P less than 0.01) and E-10-OH-NT (P less than 0.05). By contrast, there was no difference between E-10-OH-NT and placebo. This study confirms previous indications that the anticholinergic effect of E-10-OH-NT is considerably less than that of the parent drug NT.

A reversed-phase HPLC system was used to concentrate and separate components of substance P-like immunoreactivity (SP-LI) from human CSF. When CSF was injected and fractions collected, no SP-LI could be detected by radioimmunoassay (RIA) at the retention time of SP or SP-sulfoxide. Instead, SP-LI was detected in later eluting fractions. This SP-LI reacted with two different antisera raised against the C-terminal part of SP, but not with an antiserum against the N-terminal part. A compound with similar properties was also found to be present in neutral extracts of rat dorsal spinal cord. When the late-eluting compound from human CSF was treated with trypsin and rechromatographed on HPLC, an immunoreactive component eluting at the position of SP could be detected with both the C- and N-terminally directed SP antisera. These results suggest that an N-terminally extended form of SP is present in human CSF. Trypsinization also gave two other compounds with affinity for the N- but not the C-terminally directed antisera. This may indicate that N-terminal fragments of SP extended at the N-terminus or SP molecules extended at both the N- and the C-terminus (i.e., preprotachykinins) also are present in human CSF. In 32 CSF samples from depressed patients, SP-LI was determined with a C-terminally directed antiserum with and without prior HPLC separation. SP itself could not be detected, but the late-eluting form of SP-LI could be quantitated in all samples by combined HPLC-RIA. In most samples, there was a relatively good agreement between the SP-LI levels measured with and without HPLC.

The tricyclic antidepressant (TCA) tertiary amines imipramine (IMI) and amitriptyline (AMI) were found, soon after their introduction as drugs, to have active demethyl metabolites—desipramine (DMI) and nortriptyline (NT) (figure 1). These two secondary amines were later introduced as antidepressant drugs. Similarly the potent serotonin (5-HT) uptake inhibitor chlorimipramine (CI) is demethylated to an active secondary amine. In almost every patient the steady state plasma levels of demethylchlorimi-pramine (DMCI) exceeded those of the parent drug (Traskman et al., 1979; Thoren et al., 1980). As the demethyl metabolite is a potent inhibitor of norepinephrine (NE) uptake, demethylation changes the pharmacodynamic profile of the drug (Traskman et al., 1979; Thoren et al., 1980).

The metabolic ratios (MRs) between debrisoquin and 4-hydroxydebrisoquin in urine after a single oral dose of 10 mg debrisoquin were bimodally distributed in 757 healthy, white Swedish volunteers. Forty-one subjects (5.4%) had an MR greater than 12.6 and were classified as slow debrisoquin hydroxylators. The MR was reproducible in urine stored at +8 degrees C for 1 week and at -20 degrees C over a period of 5 years. Collection intervals of 6 or 12 hours gave the same MR. Intraindividual repeatability of the debrisoquin phenotyping test was established in 37 subjects examined twice at least 2 weeks apart. The calculated frequency of the single allele that is believed to control deficient debrisoquin hydroxylation is similar among white Swedish people, as among other white groups examined so far; however, it is significantly different from the frequency in certain Oriental groups. Detailed comparisons of the prevalence of slow debrisoquin hydroxylation in different ethnic groups are not possible due to shortcomings in current epidemiologic techniques used (small materials, the location of the antimode distinguishing rapid and slow hydroxylators unknown, and family studies missing).

To the Editor. —The measurement of levels of monoamine metabolites in CSF gives some information on central neurotransmission in man. As several factors affect these levels, the procedure of the lumbar puncture must be standardized. A constant volume of CSF must be drawn, because the levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) increase with increasing volume. 1-2 This is most certainly due to a fairly steep ventriculospinal CSF gradient of these two metabolites. For the norepinephrine metabolite 3-methoxy-4-hydroxyphenyl glycol (MHPG), this gradient is much less pronounced. To investigate whether the site of the lumbar puncture also is of importance for the levels of 5-HIAA and HVA, we performed lumbar punctures twice in seven healthy volunteers (men aged 25 to 46 years). The two punctures were performed at 8AMafter at least eight hours of fasting and bed rest. With the subjects in the sitting position, 6 mL of

Carbamazepine seems to as effect as phenytoin in the treatment of grand mal and psychomotor epilepsy. It is the drug of first choice in trigeminal neuralgia. After single oral doses of carbamazepine, the absorption is fairly complete and the elimination half-life is about 35 hours (range 18 to 65 hours). During multiple dosing, the half-life is decreased to 10-20 hours, probably due to autoinduction of the oxidative metabolism of the drug. Phenytoin and barbiturates also induce the metabolism of carbamazepine. After single doses of carbamazepine, elimination follows dose-dependent first order kinetics. Carbamazepine is metabolised by oxidation before excretion in the urine. In experimental animals, the metabolite carbamazepine-10,11-epoxide has anticonvulsant activity comparable with that of the parent drug. The plasma concentration of the metabolite during long-term treatment of epileptic patients varies between 5 and 81% of that of the parent drug. The plasma protein binding of the metabolite is about 50% compared with about 75% for the parent drug. Less than 50% of a given carbamazepine doses has been identified as metabolites in the urine. The quantitatively most important metabolites is the trans-10,11-dihydro-10,11-diol. The kinetics of carbamazepine have been explored to some extent in pregnant women, newborns and children. Plasma levels of carbamazepine seem to decrease during pregnancy, possibly as a result of increased metabolism. The drug readily crosses the placenta and the levels measured in newborns are comparable with maternal plasma concentrations. In newborns exposed to the drug during fetal life, the plasma half-lives were relatively short (8.2 to 28.1 hours) indicating an induction of carbamazepine metabolism during gestation. The pharmacokinetics of carbamazepine in children aged 0.3 to 15 years are comparable with that in adults. A single daily dose of carbamazepine is insufficient; 2 doses per day are appropriate in most cases, but some patients may benefit from more frequent dosing to avoid side-effects. Compared with phenytoin, for example, very few controlled studies have been performed to establish the plasma level range of carbamazepine associated with the best therapeutic outcome. However, the best anticonvulsant effect of carbamazepine seems to be obtained at plasma levels of about 5 to 10microgram/ml (20 to 40mumol/L). Side-effects are most frequent at higher levels but may also be seen at lower levels.