Ole Vendelin Olesen

Serum concentrations and side effects in psychiatric patients during risperidone therapy.

Steady state serum concentrations of risperidone and 9-hydroxyrisperidone (9-OH-risperidone), the active moiety, were measured in 42 patients. The concentration-to-dose ratios (C/D) varied by a factor of 20, from 1.8 to 36.8 (nmol/l)/(mg/24 hours), and 90% of the active moiety was constituted of 9-OH-risperidone. No correlation between the serum concentration of the active moiety and the side effects evaluated by the UKU Side Effect Scale was found. The absence of CYP2D6 (poor metabolizers) or the coadministration of drugs other than benzodiazepines increased the ratio between parent compound and metabolite but did not significantly influence the C/D of the total active moiety. A therapeutic range for serum risperidone has not been established, but 6 mg/day is considered the optimum dose for most patients. The authors found that in 90% of 22 patients administered 6 mg/day risperidone, the serum levels were within 50 to 150 nmol/l.

Olanzapine serum concentrations in psychiatric patients given standard doses: the influence of comedication.

We recorded steady state serum concentrations of olanzapine in 56 psychiatric patients under routine conditions. Twenty-two patients (39%) underwent monotherapy; the rest received additional psychotropic drugs. Doses were given once daily in the evening, and serum olanzapine levels were measured 12 hours later. For the whole group, the concentration-to-dose ratio (C/D) varied 26-fold, with a median value of 4.8 (nmol/L)/(mg/24 hours), but 80% of the patients had C/D values within the range 2 to 10 (nmol/L)/(mg/24 hours). All but three patients received standard doses (5-20 mg/24 hours), of whom 80% had serum concentrations of olanzapine within the range 22 to 146 nmol/L. Patients comedicated with potential inhibitors of CYP2D6 and other drugs displayed a median C/D approximately 40% higher than the group undergoing monotherapy. Patients comedicated with carbamazepine had a median C/D 36% lower than that of the monotherapy group. Therefore, the serum concentration range (12-hour values) of 25 to 150 nmol/L can be expected for patients receiving a standard daily dose.

Citalopram and breast-feeding: serum concentration and side effects in the infant

BACKGROUND During treatment of postpartum depression with antidepressant drugs, the mothers often strongly wish to continue breast-feeding although the long-term safety of exposing infants to low doses of antidepressants has not been established. METHODS Citalopram in breast milk and in the serum of a nursing mother and her infant was determined by high-performance liquid chromatography. RESULTS During treatment with 40 mg/day of citalopram, the concentration of the drug in milk and serum was 205 ng/mL and 98.9 ng/mL, respectively. Her infant obtained 12.7 ng/mL of citalopram in serum and uneasy sleep was observed. Sleep was normalized when the dose was halved and two breast-feedings were replaced with artificial nutrition. CONCLUSION The amount of citalopram and other selective serotonin inhibitors (SSRIs) passed to breast milk and delivered to the child correlates to the serum concentration of the mother. The lowest possible effective serum concentration should be used and breast-feeding during the drug absorption phase may be avoided.

Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations.

The authors assessed the in vitro contribution of cytochrome P450 (CYP) isoforms 1A2, 3A4, 2C9, 2C19, and 2D6 to the N‐demethylation of clozapine mediated by human liver microsomal preparations (HLM). In contrast to previous studies, the authors focused on a relatively low hepatic concentration level, 5 pM, to assess the conditions at a therapeutically relevant hepatic concentration level of clozapine. The optimal concentrations of specific inhibitors were ini‐tially established using cDNA‐expressed CYP isoforms. The mean contributions of CYPs 1A2, 2C19, 3A4, 2C9, and 2D6 amounted to 30%, 24%, 22%, 12%, and 6%, respectively, with regard to the total HLM‐mediated N‐demethylation.

Fluvoxamine-Clozapine drug interaction: inhibition in vitro of five cytochrome P450 isoforms involved in clozapine metabolism.

Administration of fluvoxamine to patients receiving clozapine therapy may increase the steady-state serum concentrations of clozapine by a factor of 5 to 10. The authors undertook in vitro studies to disclose the mechanism behind this clinically important interaction. In a human liver microsome preparation, fluvoxamine showed a concentration-dependent inhibition of clozapine N-demethylation. Fluvoxamine was much less effective as an inhibitor of clozapine N-oxidation. Fluvoxamine also inhibited in a concentration-dependent manner the activity of all five cytochrome P450 (CYP) isoforms previously determined to be capable of catalyzing the demethylation of clozapine. Fluvoxamine inhibited CYP1A2 and 2C19 with the highest affinities (Ki values of 0.041 and 0.087 microM, respectively). The Ki values for CYP2C9 and 2D6 were 2.2 and 4.9 microM, respectively, whereas the Ki for CY3A4 was 24 microM. Assuming a hepatic tissue concentration of fluvoxamine in the range of 4 to 7 microM under therapeutic conditions, a clinically significant inhibition of all but CYP3A4 is expected in relation to clozapine N-demethylation. No significant effect of fluvoxamine on clozapine N-oxidation is to be expected under therapeutic conditions. Because of the large interindividual variability of the quantity of the various CYP isoforms in liver tissue, it is not possible to predict the fluvoxamine-induced increase in the plasma concentration of clozapine of an individual patient.

Citalopram and desmethylcitalopram concentrations in breast milk and in serum of mother and infant

A case is presented with measurements of the selective serotonin reuptake inhibitor (SSRI)-antidepressant citalopram in serum of mother and breast-fed infant and in breast milk. We found a milk-to-serum concentration ratio of approximately 3 for both citalopram and the main metabolite desmethylcitalopram. Peak milk concentrations of citalopram occurred 3-9 h after drug intake by the mother. The infant received approximately 5% of the mothers dose, adjusted for weight. Accordingly, the serum level in the infant of approximately 7 nM corresponded to approximately 1/15 of the trough serum concentration of the mother (104 nM). No signs of drug effects in the infant were observed.

Free and glucuronidated olanzapine serum concentrations in psychiatric patients: Influence of carbamazepine comedication

The influence of carbamazepine on the glucuronidation of the antipsychotic olanzapine was studied in a group of psychiatric patients. Steady-state serum concentrations of free and glucuronidated olanzapine were measured in 31 psychiatric patients in monotherapy (dose range, 2.5–30 mg/d; median, 15 mg/d) and in 16 patients being comedicated with carbamazepine (dose range, 5–50 mg/d; median, 20 mg/d). The concentrations were determined by HPLC with and without acid hydrolysis of glucuronidated olanzapine. For the monotherapy group, the concentrations of free and glucuronidated olanzapine ranged from 0 nmol/L to 292 nmol/L (median, 94 nmol/L) and from 0 nmol/L to 180 nmol/L (median, 27 nmol/L), respectively. The serum concentrations of the carbamazepine-treated group ranged from 21 nmol/L to 310 nmol/L (median, 81 nmol/L) and from 0 to 376 nmol/L (median, 57 nmol/L) for free and glucuronidated olanzapine, respectively. Two patients with outlying values were excluded from further analysis. The median concentration-to-daily dose ratios (C/D) of free and glucuronidated olanzapine in the monotherapy group were 5.8 nmol/L/mg and 2.2 nmol/L/mg, respectively (n =30). The corresponding values for the group comedicated with carbamazepine were 3.6 and 3.1 nmol/L/mg (n =15). Thus, the median C/D of free olanzapine in the carbamazepine group was 38% lower than that of the monotherapy group (P <0.01), confirming that carbamazepine accelerates the metabolism of olanzapine. Further, for the carbamazepine group the median glucuronidated olanzapine fraction constituted 79% of the free fraction compared with 43% for the monotherapy group (P <0.01), which suggests that an increased rate of olanzapine glucuronidation contributes to the increased rate of metabolism of olanzapine induced by carbamazepine.

Renal Lithium Clearance as a Measure of the Delivery of Water and Sodium from the Proximal Tubule in Humans

The delivery of tubular fluid from the proximal straight tubule to the thin descending limb of the loop of Henle was measured in nine volunteers by the lithium clearance method and by the water diuresis method. Lithium clearance and urine flow during water diuresis varied in proportion to each other with a high degree of correlation (r = 0.93, p < 0.001). The proportionality between lithium clearance and urine flow was unaffected by variations in fractional sodium excretion. The results support the assumption that lithium clearance can be used as a measure of the delivery of tubular fluid from the proximal tubule in humans with sodium intakes within the normal range.

Fully automated on-line determination of olanzapine in serum for routine therapeutic drug monitoring.

A method is presented for unattended fully automated extraction and on-line determination of the atypical antipsychotic drug olanzapine in serum. An ASPEC automatic sample-preparing apparatus with Isolute cyanopropyl-bonded silicagel cartridges was used for solid-phase extraction of the drugs from serum. The adsorbed drugs were eluted with methanol and an aliquot injected into a high-performance liquid chromatograph (HPLC) apparatus. Trifluoperazine was used as internal standard, and the analytes were separated on an unmodified silicagel column using methanol–ammonium acetate buffer pH 9.9 (85:15) as mobile phase. Ultraviolet detection at 257 nm was used for quantitation. Within the therapeutic range for the serum concentration of olanzapine, the interday variations for the quantitative determinations were <8%. Comparisons between concentrations measured using liquid–liquid extraction and the present on-line extraction method showed good agreement. Other drugs often used in combination with olanzapine did not interfere with the quantitative determinations. The method has been in routine use for more than 1 year for therapeutic drug monitoring.

Effect of Anaesthesia and Surgery on Urine Flow and Electrolyte Excretion in Different Rat Strains

The suitability of some commonly used experimental procedures for studying the effect of chronic alterations of sodium excretion on lithium clearance was examined in Wistar rats and Sprague-Dawley rats. The animals were maintained on diets with standardized sodium content for 10 days before the investigation. Urine flow and clearance values were measured in (1) awake unoperated rats, (2) awake catheterized rats and (3) anaesthetized rats of both strains. Awake unoperated and awake catheterized Wistar rats showed almost identical urine flows and clearances of sodium and lithium. Amytal anaesthetized Wistar rats showed significantly depressed urine flows and clearances of sodium, lithium and inulin as compared with awake rats. Awake unoperated and awake catheterized Sprague-Dawley rats showed almost identical clearance values but the urine flow rates were increased about fivefold in the awake catheterized Sprague-Dawley rats. Amytal anaesthetized catheterized Sprague-Dawley rats showed unchanged urine flows and clearance values as compared with awake rats. Inactin anaesthesia reduced the urine flows and clearance values in both Wistar rats and Sprague-Dawley rats. It is concluded that anaesthesia and surgery affect the kidney function to different degrees in different rat strains, amytal anaesthetized Sprague-Dawley rats being the least influenced. If exposure of the kidney is unnecessary, awake catheterized Wistar rats offer a suitable experimental procedure for determination of urine flow and urinary clearances of sodium and lithium.