Kim Brøsen

Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms.

The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.

Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine

The analgesic efficacy and kinetics of a single oral dose of 75 mg codeine was investigated in 12 extensive metabolizers and 12 poor metabolizers of sparteine in a double‐blind, placebo‐controlled crossover study. The cosegregation of the O‐demethylation of codeine to morphine with the sparteine oxidation polymorphism was confirmed. Hence morphine could not be detected in the plasma of any of the poor metabolizers, whereas detectable morphine plasma levels were found in 10 of 12 extensive metabolizers. Pain thresholds to laser stimuli were determined before drug intake and 90, 150, and 210 minutes after drug intake. Codeine significantly increased the pricking pain thresholds in the extensive metabolizers (p < 0.05), whereas there were no significant changes in the poor metabolizers. No change in pain thresholds occurred with placebo in any of the two phenotypes. In the extensive metabolizers there was a significant positive correlation between the increase in pain threshold and plasma concentration of codeine. The study supports the hypothesis that morphine formation is essential for achievement of analgesia during codeine treatment.

Citalopram: interaction studies with levomepromazine, imipramine, and lithium.

The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20–31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases—one with citalopram alone, one with one of the three other drugs alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a nonenantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10–20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused ∼50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethyl-citalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.

Interaction between tramadol and phenprocoumon

We report an interaction between phenprocoumon (Marcoumar) and tramadol which led to an increase in International Normalised Ratio (INR) in two patients. A 54-year-old woman, otherwise healthy, with a suspected deep venous thrombosis in the left lower leg, was begun on heparin (10 000 IU twice daily) and phenprocoumon monitored by INR (therapeutic target range 2–3). Treatment was stopped after 2 days, because the diagnosis of deep venous thrombosis was not confirmed by ultrasonography. Tramadol (Nobligan, Grunenthal, Grunenthal GmbH, Aachen, Germany) 50–100 mg four times daily was given from day 3 for low back pain (figure). Her only other medication was paracetamol 1 g four times daily. As the INR kept rising despite withdrawal of phenprocoumon, phytomenadione (vitamin K1) 2 mg (day 5) and 5 mg (days 9–11) was given orally and the INR gradually fell to 0·9 (figure). On day 6, she had a nosebleed (INR 4·0). A 66-year-old woman with idiopathic lung fibrosis was admitted after a fall that resulted in fracture of a lumbar vertebra. Tramadol (Dolol, Nocomed Christianes, Chausee de Gand, Brussels, Belgium) 100 mg four times daily was prescribed for pain. Her other medication included estazolam 250 mg four times daily, diflunisal 50 mg three times daily, oxazepam 30 mg daily, calcium (400 mg) and vitamin D (5 g) twice daily, and paracetamol 1 g four times daily. 1 month later, she had a pulmonary embolism after an endoscopic retrograde cholangiopancreaticography, and treatment with heparin (12 500 IU twice daily) and phenprocoumon was begun. A rise in INR was seen and on day 6 phytomenadione 2 mg was given intramuscularly. Tramadol was stopped on day 8 and 3 days later, INR was stable at about 2 (figure). Albumin concentration, prothrombin time, and plasma transaminases were normal in both patients. Apart from tramadol, none of the prescribed drugs was suspected of affecting the anticoagulant effect of phenprocoumon. A pharmacodynamic interaction in which tramadol potentiated the action of phenprocoumon on vitamin K epoxide reductase may have caused the prolonged rise in INR. Several pharmacokinetic mechanisms are also possible. Increased absorption of phenprocoumon is unlikely because phenprocoumon is almost completely absorbed. An interaction caused by protein displacement of phenprocoumon (plasma protein binding 98–99%) and tramadol (plasma protein binding 20%) is unlikely because of the low protein binding of tramadol. A change in apparent volume of distribution is unlikely too, as none of the patients were oedematous at any time and both had normal serum creatinine. Tramadol is metabolised by CYP2D6, and phenprocoumon is probably metabolised by CYP2C9 but even so, we think the most likely mechanism for this interaction is inhibition of phenprocoumon metabolism in the liver by tramadol or one of its metabolites, as described for the drug interaction between warfarin and phenylbutazone. If tramadol is widely prescribed to older people taking anticoagulants this interaction should be monitored by frequent INR measurements. This advice also applies to warfarin, because adverse reports to the Danish Medicines Agency’s Committee on Adverse Drug Reactions suggest that tramadol increases the effect of both warfarin (three reports) and phenprocoumon (two reports).

Implementation of a rational pharmacotherapy intervention for inpatients at a psychiatric department

The objective of the study was to develop, implement and evaluate two treatment algorithms for schizophrenia and depression at a psychiatric hospital department. The treatment algorithms were based on available literature and developed in collaboration between psychiatrists, clinical pharmacologists and a clinical pharmacist. The treatment algorithms were introduced at a meeting for all psychiatrists, reinforced by the project psychiatrists in the daily routine and used for educational purposes of young doctors and medical students. A quantitative pre–post evaluation was conducted using data from medical charts, and qualitative information was collected by interviews. In general, no significant differences were found when comparing outcomes from 104 charts from the baseline period with 96 charts from the post-intervention period. Most of the patients (65% in the post-intervention period) admitted during the data collection periods did not receive any medication changes. Of the patients undergoing medication changes in the post-intervention period, 56% followed the algorithms, and 70% of the patients admitted to the psychiatric hospital department for the first time had their medications changed according to the algorithms. All of the 10 interviewed doctors found the algorithms useful. The treatment algorithms were successfully implemented with a high degree of satisfaction among the interviewed doctors. The majority of patients admitted to the psychiatric hospital department for the first time had their medications changed according to the algorithms.