Jan-Olof Svensson

Disposition of fluvoxamine in humans is determined by the polymorphic CYP2D6 and also by the CYP1A2 activity

Fluvoxamine is a selective serotonin reuptake inhibitor used widely in the treatment of depression and other psychiatric diseases, but little is known about the specific isozymes involved in its metabolism. This study investigated the relationship between fluvoxamine disposition and the polymorphic CYP2D6 and the polycyclic aromatic hydrocarbon (as contained in cigarette smoke) inducible CYP1A2.

Efavirenz plasma concentrations in HIV-infected patients: inter- and intraindividual variability and clinical effects.

Efavirenz is a drug subject to extensive metabolism, mainly by the cytochrome P-450 isoenzyme CYP2B6, known to exhibit extensive interindividual variability. The aim of the present study was 2-fold: to investigate the relationship between plasma concentration and clinical effects of efavirenz and to investigate the extent of the inter- and intraindividual variability of the plasma concentration measurements. From an open clinic, 68 HIV-positive patients on efavirenz-containing treatment were recruited. From each patient 1 to 5 samples were collected; 43 had more than 1 sample taken. Most samples were taken 10–24 hours after the latest dose. Efavirenz was analyzed by high-performance liquid chromatography with UV detection. The data were analyzed by the variance component model analysis of variance. Efavirenz concentrations were reproducible, and intraindividual variability constituted only 16% of the total variance. Thus, 84% of the variance was attributed to interindividual variability. The incidence of primary treatment failure was related to low plasma concentrations with a geometric mean concentration of 6.1 μmol/L compared with 8.7 μmol/L in those responding to therapy (P < 0.05). If a cutoff of 7 μmol/L is used, 10 of 13 failing to respond were below this level compared with 15 of 45 in those responding. It is concluded that efavirenz plasma concentration measurement gives reproducible results predictive of primary treatment failure. A lower bound for the therapeutic level of 7 μmol/L is proposed, and data from other authors suggests that an upper level of 13 μmol/L may be applied.

Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test.

The ultrarapid metabolizer phenotype of the cytochrome P4502D6 (CYP2D6) enzyme has been considered a relevant cause of nonresponse to antidepressant drug therapy. Prescribing high doses of antidepressants to such patients leads to high concentrations of potentially toxic metabolites and an increased risk for adverse reactions. Normalization of the metabolic status of ultrarapid metabolizers by inhibition of CYP2D6 activity could offer a clinically acceptable method to successfully treat such patients with antidepressants.

Determination of ribavirin in serum using highly selective solid-phase extraction and high-performance liquid chromatography.

A rapid assay for determination of ribavirin in serum using solid-phase extraction (SPE), high-performance liquid chromatography (HPLC), and UV-detection was developed. The SPE uses phenylboronic acid columns with an approximately 100% recovery for ribavirin. The concentration-peak area relation was linear (r > 0.995), from 1 to 64 microM in 100 microL serum. The limit of detection was 0.1 microM. The intraassay CV was 3.2% at treatment levels (9.7 microM) and 11.5% at 0.4 microM. The method is used to monitor patients undergoing ribavirin treatment for hepatitis C (HCV). Samples from HCV-infected patients with and without renal dysfunction have been analyzed without interference of endogenous compounds. It is concluded that the method is useful for routine therapeutic drug monitoring.

Determination of Rapamycin in Whole Blood by HPLC

Sirolimus (rapamycin, RAPA) is a natural fermentation product (macrolide antibiotic) that has demonstrated potent immunosuppressive activity. A reverse-phase high-performance liquid chromatographic (HPLC) method is described for analysis of the drug in whole blood. The samples are purified by using liquid-liquid extraction with butyl chloride/diethyl ether combined with reversed-phase solid-phase extraction. RAPA and internal standard were traced by UV-detection at 278 nm. Linear calibration curves with correlation coefficients > 0.999 were obtained (range, 1-50 ng/ml). Minimum detectable concentration was approximately 0.4 ng/ml and recovery approximately 45% for both RAPA and internal standard. Coefficient of variation (day to day) was 9.8% at 5 ng/ml (n = 6) and 5.6% at 40 ng/ml (n = 6). The chromatography requires < 10 min per sample. The assay has proved to be free of interference peaks from cyclosporine or tacrolimus. The method has been used to determine the whole blood concentrations in samples from healthy volunteers and renal transplant recipients receiving single and multiple doses of oral rapamycin.

Nonlinearity of amoxicillin absorption kinetics in human

SummarySpecialised gastrointestinal absorption of amoxicillin has been suggested in man and has been demonstrated in animals. In order to study the rate and extent of amoxicillin absorption, six healthy subjects were given 500 mg IV and two oral doses (500 mg and 3 g as a suspension). Absorption kinetics was analysed by compartmental modelling, noncompartmental methods and by calculation of absorption rates using deconvolution.Dose-dependency of the extent of amoxicillin absorption was observed, with a lower than expected mean maximum plasma concentration (49%), and fraction of the dose absorbed (39%) after the 3 g dose calculated from the 500 mg dose, assuming kinetic linearity. Zero-order kinetics of absorption was apparent in some subjects after the 500 mg dose, both from model fitting and absorption rate profile. However, no pattern consistent with pure first-order or zero-order absorption was observed after both oral doses in any individual. The dose-dependency of amoxicillin absorption was confirmed by a trend to an increased time of absorption for the high dose.The results show the variable nature and nonlinearity of the gastrointestinal absorption of amoxicillin and indicate the involvement of a number of factors, in addition to simple diffusion.

The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans

Background: Ketamine in sub‐dissociative doses has been shown to have analgesic and phantom‐Limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain‐generating mechanisms are not well understood.

Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators

The O-demethylation of codeine is polymorphic and catalyzed by CYP2D6. The metabolites of codeine formed through O- and N-demethylation as well as glucuronidation were quantified in the ultrarapid metabolizers of debrisoquine and compared with the normal extensive (EM) and poor metabolizers (PM). The urinary codeine and its seven metabolites were detected after 25 mg codeine in 24 healthy Caucasian subjects with low debrisoquine metabolic ratios (MR, < or = 0.11) and a group of 132 subjects tested earlier with codeine and debrisoquine including 114 EMs (MR < 12.6) and 18 PMs (MR > 12.6). Whereas the O-demethylated metabolites accounted for < 0.4% of the total recovery on average in the PMs and 1.7% to 8.7% in the EMs, they accounted for 15.3% in the 24 subjects with ultrarapid metabolism of debrisoquine. This study suggests that the ultrarapid debrisoquine hydroxylators may develop increased O-demethylated metabolite-dependent effects or side-effects of codeine.

A simple HPLC method for simultaneous determination of mycophenolic acid and mycophenolic acid glucuronide in plasma.

A reversed-phase high-performance liquid chromatographic method for the simultaneous determination of mycophenolic acid and its metabolite, mycophenolic acid glucuronide, is presented herein. Sample purification is limited to protein precipitation with acetonitrile. The analytes were separated on a C18 column with a mobile phase containing 30% acetonitrile and a 40 mm phosphoric acid buffer at pH 2.1 and measured with UV-detection at 215 nm.

Determination of acyclovir and its metabolite 9-carboxymethoxymethylguanine in serum and urine using solid-phase extraction and high-performance liquid chromatography

A reversed-phase ion-pair high-performance liquid chromatography method for the determination of acyclovir and its metabolite 9-carboxymethoxymethylguanine is described. The sample are purified by reversed-phase solid-phase extraction. The components are separated on a C18 column with a mobile phase containing 18% acetonitrile, 5 mM dodecyl sulphate and 30 mM phosphate buffer, pH 2.1, and measured by fluorescence detection using an excitation wavelength of 285 nm and an emission wavelength of 380 nm. Detection limits are 0.12 microM (plasma) and 0.60 microM (urine) for acyclovir, and 0.26 microM (plasma) and 1.3 microM (urine) for metabolite. Correlation coefficients that were better than 0.998 were obtained normally. This analytical method, which enables simultaneous measurement of parent compound and metabolite, has been used in kinetics studies and for therapeutic drug monitoring in different patient groups with variable degrees of renal dysfunction.