Ulf Bondesson

Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine : evidence from a therapeutic drug monitoring service

Therapeutic drug monitoring data for clozapine were used to study interactions with other drugs. The distribution of the ratio concentration/dose (C/D) of clozapine was compared in four matched groups—patients simultaneously treated with benzodiazepines, patients on drugs that inhibit the cytochrome P450 enzyme CYP2D6, patients taking carbamazepine, and those not taking any of these drugs. No difference was seen among the monotherapy, CYP2D6, and benzodiazepine groups. Patients on carbamazepine had a mean 50% lower C/D than the monotherapy group (p < 0.001), indicating that carbamazepine is an inducer of the metabolism of clozapine. The C/D was inversely correlated to the daily dose of carbamazepine. Intraindividual comparisons in eight patients, with analyses both on and off carbamazepine, confirmed a substantial decrease of the clozapine concentration when carbamazepine was introduced. Four patients treated with clozapine were concomitantly given the antidepressant fluvoxamine. Three of them exhibited a much higher C/D ratio when on fluvoxamine compared with the monotherapy group. Two had their clozapine levels analyzed when on and off fluvoxamine. The dose-normalized clozapine concentration increased by a factor of 5–10 when fluvoxamine was added. We conclude that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels. The pathways are not known with certainty, but CYP1A2 may be of major importance for the metabolism of clozapine, since fluvoxamine is a potent inhibitor of this enzyme. A recent panel study suggests that determination of CYP1A2 activity with the caffeine test may be very useful for the dosing of clozapine. The induction of clozapine metabolism by carbamazepine might be partly mediated by CYP3A4.

Patient-controlled Analgesic Therapy, Part III: Pharmacokinetics and Analgesic Plasma Concentrations of Ketobemidone

SummaryThe effects of anaesthesia and surgery on the pharmacokinetics of ketobemidone were studied in 12 patients. Plasma ketobemidone concentrations were assayed with a mass-fragmentographic method. The peroperative Vdarea was 5.9±2.6L/kg and the terminal half-life was 3.9 ± 1.7h. In the postoperative period Vdarea decreased to 3.7 ±0.4L/kg and the terminal half-life to 2.1 ±0.4h. Plasma clearance (Clp) did not change significantly, peroperative Clp being 18±4.3ml/min/kg and postoperative Clp being 22 ±7.5ml/min/kg. The pharmacokinetics of ketobemidone were not influenced by the addition of a spasmolytic agent in the commercial combination ketobemidone preparation ‘Ketogin’.Postoperative pain was relieved in 15 patients by patient-controlled intravenous administration of ketobemidone by means of a programmable drug injector. The mean ketobemidone consumption was 2.3 ± 0.8mg/h, which produced a mean plasma concentration of 28 ± 11ng/ml. Pseudosteady-state plasma concentrations of ketobemidone were established with a mean minimum effective concentration (MEC) of 25 ± 11ng/ml. Ketobemidone ‘plain’ and ‘Ketogin’ did not differ significantly in these respects. Analgesia was considered by all patients to be satisfactory.

St John's Wort Decreases the Bioavailability of R- and S-verapamil Through Induction of the First-pass Metabolism

Our objective was to investigate the inducing effect of repeated oral administration of St Johns wort on the jejunal transport and presystemic extraction of R‐ and S‐verapamil in humans.

Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration

SummaryPlasma concentrations of codeine and its demethylated metabolite, morphine, were determined after single and repeated oral administration of codeine. Twelve healthy volunteers received two doses of codeine 60 mg, 2.8 h apart. In order to achieve steady-state conditions codeine 60 mg was then taken every 8 h for a further five doses. The plasma concentrations of codeine and morphine after the first, second and seventh doses were analyzed by GC-MS. The maximum plasma concentrations of codeine and morphine were reached about 1 h after administration and this time interval did not change on repeated administration. The peak plasma codeine was higher after the second dose of codeine than after the first and the concentration resembled that at steady-state. For morphine, the plasma concentration did not increase significantly after the second dose. Both after a single dose and during steady-state the plasma concentration of morphine was only 2–3% of that of codeine. It seems unlikely that morphine plays a significant role in the analgesic efficacy of single or repeated doses of codeine.

Determination of clozapine and its N-demethylated metabolite in plasma by use of gas chromatography-mass spectrometry with single ion detection

A gas chromatographic-mass spectrometric method with single ion detection has been developed for determination of clozapine and its N-demethylated metabolite norclozapine in plasma. Propylnorclozapine was used as internal standard and the mass spectrometer was adjusted to record the ion m/z 373 for the compounds analyzed. The precision of the method was found to be high, with a relative standard deviation of 6% or less for replicated samples. The limit of determination was 1.0 ng/ml for clozapine and 5.0 ng/ml norclozapine. A significant correlation was obtained between the daily oral dose of clozapine within the dose interval 100–800 mg/day and the plasma level of clozapine in 22 chronic schizophrenic patients. The plasma levels of clozapine and norclozapine were also significantly correlated. The quotient norclozapine/clozapine showed great interindividual variation and was not correlated to the daily dose of clozapine. The method is rapid and sensitive to allow evaluation of the pharmacokinetic properties of clozapine in the treatment of schizophrenic patients.

Clinical pharmacokinetics of clozapine in chronic schizophrenic patients.

SummaryThe clinical pharmacokinetics of clozapine, an atypical neuroleptic, was evaluated in 10 chronic schizophrenic male patients after intravenous and oral administration. The mean equilibrium-state concentration ratio between blood and plasma was experimentally determined to be 0.87. The average values for blood clearance, hepatic extraction ratio and oral bioavailability were 250 ml/min, 0.2 and 0.27, respectively. Plasma concentration peaked on average at 3 h. The mean volume of distribution at steady-state and the terminal half-life was 1.6 l/kg and 10.3 h, respectively. A large fraction of the dose is most probably metabolized by some extrahepatic presystemic routes. The large inter-individual variability in the bioavailability and clearance is probably the main reason for large variation in the steady-state plasma level in patients receiving the same oral dosage regimen.

Multiple transport mechanisms involved in the intestinal absorption and first-pass extraction of fexofenadine.

Our objective was to investigate the main in vivo transport mechanisms of fexofenadine involved in the intestinal absorption and bioavailability of the drug in humans.

Oxaliplatin Degradation in the Presence of Chloride-Identification and Cytotoxicity of the Monochloro Monooxalato Complex

AbstractPurpose. To study the degradation of oxaliplatin in chloride media and evaluate the cytotoxicity of oxaliplatin in normal and chloride-deficient medium. Methods. The products of the reaction of oxaliplatin with chloride were separated on a Hypercarb S column with a mobile phase containing 40% methanol in 0.05 M ammonia and subjected to electrospray ionization mass spectrometry. The cytotoxicity of oxaliplatin in normal and chloride-deficient medium was evaluated by 30-min incubations on human colon adenocarcinoma cells (HT-29). Results. We identified a new intermediate degradation product, the monochloro monooxalato complex ([Pt(dach)oxCl]−) and the final product, the dichloro complex (Pt(dach)Cl2), by liquid chromatography-mass spectrometry. [Pt(dach)oxCl]− was found as the negative ion, M−, at m/z 431, and the positive ion, [M+2H]+, m/z 433. Pt(dach)Cl2 was found as the negative ion, [M-H]−, m/z 377, and the positive ion, [M+NH4]+, m/z 396. The fast initial degradation of oxaliplatin can be coupled to the fast formation of [Pt(dach)oxCl]−. In the cytotoxic assay, the cell survival was not affected by the chloride levels. Conclusions. [Pt(dach)oxCl]−, a new transformation product of oxaliplatin, has been identified. Its in vitro cytotoxic effect does not appear to exceed that of oxaliplatin.

Simultaneous analysis of endogenous neurotransmitters and neuropeptides in brain tissue using capillary electrophoresis - microelectrospray-tandem mass spectrometry

Capillary electrophoresis was combined with highly sensitive microelectrospray‐tandem mass spectrometry to simultaneously detect classical small molecule neurotransmitters as well as neuropeptides from discrete regions of the marmoset brain. A mixture of four classical neurotransmitters (glutamate, γ‐aminobutyric acid, acetylcholine, dopamine) and four neuropeptides (neurotensin, methionine‐enkephalin, leucine‐enkephalin and substance P 1—7) was studied to optimize the capillary electrophoresis conditions for separation, injection volume, and analysis time. γ‐Aminopropyltriethoxysilane‐coated capillaries and acetic acid electrolytes were used to avoid interactions between the sample and the capillary surface and to obtain a high anodic electroosmotic flow, which resulted in a short analysis time. Detection was performed using tandem mass spectrometry in the selected reaction monitoring mode using a triple quadrupole mass spectrometer. Samples were dissolved in ammonium acetate to achieve a transient‐isotachophoretic concentration step at the beginning of the separation and to make it possible to inject larger sample volumes, up to 140 nL. Small amounts of tissue from specific regions of the marmoset monkey brain were pretreated using solid‐phase extraction as a clean‐up and concentrating step. In the striatum we could detect endogenous glutamate, γ‐aminobutyric acid (GABA), acetylcholine and dopamine, as well as the neuropeptides methionine‐enkephalin and substance P 1—7 in the same analysis, using only 58 mm3 of brain tissue.

Analysis of buprenorphine and its n-dealkylated metabolite in plasma and urine by selected-ion monitoring

A selected-ion monitoring method was developed for determination of buprenorphine and its N-dealkylated metabolite (norbuprenorphine) in human plasma and urine. N-Propylnorbuprenorphine was added as internal standard to 2-3 ml of sample and the alkaloids were extracted with toluene-2 butanol at pH 9.4. After back-extraction in dilute sulphuric acid, the compounds were heated at 110 degrees C. This procedure led to quantitative loss of methanol followed by ring formation between the 6-methoxy group and the branched side-chain of all compounds. The derivatives were extracted into dichloromethane-2-butanol and treated with pentafluoropropionic anhydride. The resulting derivatives were suitable for selected-ion monitoring analysis. The coefficient of variation was found to be 4.5% at 5 ng/ml and 8.9% at 50 ng/ml in urine. The corresponding values for plasma were 6.2% and 5.3%, respectively. The lower limit of detection in plasma was 150 pg/ml, permitting analysis of plasma levels of buprenorphine for 24 h and urine levels of buprenorphine and norbuprenorphine for more than seven days after a therapeutic dose of buprenorphine. This method is the first with sufficient specificity and sensitivity for characterization of the clinical pharmacokinetics of buprenorphine.