T Villén

Karolinska Institutet, Stockholm, Stockholm, Sweden

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Publications (13)47.18 Total impact

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    ABSTRACT: The presence of morphine in a urinary sample may be caused not only by intake of heroin but also by intake of poppy-seed-containing food shortly before urine sampling or intake of drugs containing morphine, ethyl morphine, or codeine. To facilitate the interpretation, the heroin-specific metabolite 6-monoacetylmorphine (6-MAM) can be analyzed along with morphine-3-glucuronide (M3G) in an LC-MS verification analysis. In sporadic samples positive in the immunologic opiate screening test, 6-MAM, but not M3G, was found. To systematically analyze the finding all specimens with positive 6-MAM and/or M3G found during a 1-year period were investigated (n = 1923). Of these, 423 were positive for 6-MAM. In 32 (7.6%) of the samples 6-MAM was detected while the M3G concentrations were below cutoff (300 ng/mL) and in some cases even below the limit of detection (15 ng/mL). The 32 samples with this excretion pattern came from 13 different individuals, all but one with previously known heroin abuse. Eleven urine samples, nine containing M3G and 6-MAM and two with only 6-MAM, were also analyzed for the presence of heroin. In six samples, including the two with only 6-MAM, heroin was detected. There are several plausible explanations for these findings. The intake may have taken place shortly before urine sampling. High concentrations of heroin and 6-MAM may inhibit UGT 2B7, the enzyme responsible for glucuronidation of morphine. The hydrolyzation of 6-MAM to morphine may be disturbed by either internal or external causes. To elucidate this, further studies are required. Nevertheless, our finding demonstrates that routine measurement of 6-MAM when verifying opioid-positive immunologic screening results facilitates interpretation of low concentrations of M3G in urine specimens.
    Therapeutic Drug Monitoring 11/2003; 25(5):645-8. · 2.23 Impact Factor
  • Journal of Chromatography A 03/1993; 612(2):336-7; discussion 338-9. · 4.61 Impact Factor
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    ABSTRACT: 1. Hearing impairment was investigated in six healthy volunteers who received oral doses of 5, 10 and 15 mg kg-1 quinine single-blind and in random order. 2. The plasma concentration of quinine was followed for 48 h and the time course was fitted by a linear one compartment pharmacokinetic model. 3. Hearing thresholds were measured by pure tone audiometry. There was a delay between impairment in hearing and change in plasma quinine concentration. Thus the method of effect compartment modelling was applied. 4. The effect on hearing (L), measured as a shift in hearing threshold (dB), was used to estimate the rate constant for elimination of drug from the assumed effect compartment (ke0) and two parameters specifying the effect model (gamma and k). The effect model applied was L = 10 (log k + gamma x log Ce) where Ce is the calculated drug concentration in the effect compartment. This model is a logarithmic transform of a power expression equivalent to the Hill equation at the lower end of the effect range. In all experiments where there was a clear effect on hearing, convergence on a set of parameter estimates occurred, but inter- and intraindividual variability was large. The mean value of ke0 was 3.32 +/- 5.93 h-1 s.d., for gamma it was 1.73 +/- 1.14 s.d. and for k it was 0.59 +/- 0.66 s.d.
    British Journal of Clinical Pharmacology 05/1991; 31(4):409-12. · 3.69 Impact Factor
  • Y A Abdi, T Villén
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    ABSTRACT: Six male healthy volunteers were given single oral doses of 7.5 mg/kg of metrifonate and concentrations of metrifonate and dichlorvos were determined in whole blood using a standardized sampling procedure. Blood was collected in test tubes containing equal volumes of 0.74 M phosphoric acid for the determinations of metrifonate and dichlorvos with gas chromatography and mass spectrometry at different time points for up to 24 hr. Cholinesterases were also determined in blood haemolyzed with water. Metrifonate was quickly absorbed with a Cmax of 50.5 +/- 18.9 mumol/l which was obtained between 0.17 to 1 hr after drug intake. Mean whole blood t1/2, Clo and AUC were 2.07 +/- 0.24 hr, 0.34 +/- 0.06 l/hr/kg and 89.2 +/- 16 mumol.hr/l respectively. The concentrations of dichlorvos closely followed those of metrifonate with a constant ratio of 0.01 to 0.02. The concentrations of metrifonate were detectable for up to 8 hr but those of dichlorvos had fallen below the level of determination by this time. Both plasma and red blood cell cholinesterases were readily inhibited and were still low after 24 hr. None of the volunteers complained of side effects.
    Pharmacology &amp Toxicology 03/1991; 68(2):137-9.
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    ABSTRACT: The total concentration of ethosuximide varied between 80 and 770 mumol/L in plasma samples obtained from 33 patients on long-term treatment with the racemic drug. The ratios between the two enantiomers measured by chiral gas chromatography in the same samples were close to unity (mean +/- SD = 1.06 +/- 0.14; range = 0.76-1.39). This suggests that the disposition of ethosuximide in humans is not stereoselective and that the measurement of total concentrations of ethosuximide is sufficient for therapeutic monitoring.
    Therapeutic Drug Monitoring 10/1990; 12(5):514-6. · 2.23 Impact Factor
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    ABSTRACT: Analytical methods for determining metrifonate and dichlorvos in whole blood and a sampling procedure suitable for pharmacokinetic studies in man are described. Metrifonate concentrations were determined after chloroform extraction using gas chromatography-nitrogen-phosphorus detection. The within-assay coefficients of variation were 4 and 9% at 19.4 and 0.8 mumol/l (limits of determination), respectively. Dichlorvos was determined using gas chromatography-mass spectrometry of toluene extracts. The within-assay coefficients of variation were 2 and 5% at 225 and 50 nmol/l (limits of determination), respectively. Since both substances are chemically unstable, the blood was collected by dripping it directly from the vein into 0.74 M phosphoric acid.
    Journal of Chromatography A 09/1990; 529(2):309-17. · 4.61 Impact Factor
  • U Hellgren, T Villén, O Ericsson
    Journal of Chromatography A 07/1990; 528(1):221-7. · 4.61 Impact Factor
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    ABSTRACT: 1. Frusemide was given intravenously at a dose of 5 mg kg-1 to five healthy volunteers and the diuresis was assessed by frequent spontaneous voiding over 5 h. Urinary volume and contents of sodium, chloride, potassium and frusemide were measured. 2. Diuretic response was evaluated using the sigmoid Emax model and non linear regression of diuresis vs frusemide excretion rate. The time courses of diuresis (pharmacological effect) and diuretic efficiency were constructed from the fitted parameters of the sigmoid Emax model. 3. The frusemide excretion rate associated with maximum efficiency was found, as predicted theoretically, to be less than the excretion rate associated with 50% of maximum effect in four of the five subjects in whom the slope factor was less than 2. 4. The effect over time is dependent both on the instantaneous drug effect but also on its pharmacokinetic properties and mode of administration. An intravenous bolus is the least efficient mode of administration while a controlled input producing a frusemide excretion at maximum efficiency should yield up to a 2.3 times higher diuretic response.
    British Journal of Clinical Pharmacology 03/1990; 29(2):215-9. · 3.69 Impact Factor
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    ABSTRACT: Metrifonate concentrations in plasma, its inhibition of blood cholinesterase, and side-effects were studied in 16 healthy volunteers who received a single oral dose of 2.5, 5, 7.5 or 15 mg/kg in a randomized double-blind study (4 subjects for each dose). Metrifonate was determined by a gas chromatographic method. Peak plasma levels were reached within 2 hours; the half-life in plasma, oral clearance, and normalized Cmax and AUCs did not differ significantly between the four groups. Plasma cholinesterase (BuchE) was inhibited to low levels in all subjects, while erythrocyte cholinesterase (AchE) was affected in a dose-dependent fashion. The occurrence of side-effects correlated strongly with peak plasma levels but not with maximum AchE inhibition or with increase in salivation. This study shows that the absorption of metrifonate was not significantly different for doses between 2.5 and 15 mg/kg. The plasma levels of this drug correlated with the occurrence of side-effects.
    Bulletin of the World Health Organisation 02/1990; 68(6):731-6. · 5.25 Impact Factor
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    E J Sanz, T Villén, C Alm, L Bertilsson
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    ABSTRACT: 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 &#38 Therapeutics 06/1989; 45(5):495-9. · 6.85 Impact Factor
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    ABSTRACT: Single oral 10 mg doses of diazepam and demethyldiazepam were given on different occasions to 16 healthy subjects. The subjects included four poor hydroxylators of debrisoquin and three poor hydroxylators of mephenytoin. There was a correlation between the total plasma clearance of diazepam and demethyldiazepam (rs = 0.83; p less than 0.01). There was no relationship between benzodiazepine disposition and debrisoquin hydroxylation. Poor hydroxylators of mephenytoin had less than half the plasma clearance of both diazepam (p = 0.0008) and demethyldiazepam (p = 0.0001) compared with extensive hydroxylators of mephenytoin. The plasma half-lives were longer in poor hydroxylators than they were in extensive hydroxylators of mephenytoin for both diazepam (88.3 +/- SD 17.2 and 40.8 +/- 14.0 hours; p = 0.0002) and demethyldiazepam (127.8 +/- 23.0 and 59.0 +/- 16.8 hours; p = 0.0001). There was no significant difference in volume of distribution of the benzodiazepines between the phenotypes. This study shows that the metabolism of both diazepam (mainly demethylation) and demethyldiazepam (mainly hydroxylation) is related to the mephenytoin, but not to the debrisoquin, hydroxylation phenotype.
    Clinical Pharmacology &#38 Therapeutics 05/1989; 45(4):348-55. · 6.85 Impact Factor
  • G Alván, K K Karlsson, T Villén
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    ABSTRACT: The hearing ability was measured in anaesthetised guinea pigs by recording cochlear evoked potentials induced by standardised sound stimulation. The animals were given quinine intravenously and blood samples were withdrawn for assay of quinine. The shift in hearing threshold was closely related to the quinine blood concentration. The effect-concentration relationships were analysed according to the equation L = 10 (log k+a.log (s-b] which can be viewed as a special case of the Hill equation assuming that the stimulation (s) is of very low intensity compared to the stimulus at which half of the maximum response would be obtained and introducing an absolute limit for a stimulus at which no response is obtained.
    Life Sciences 02/1989; 45(8):751-5. · 2.56 Impact Factor
  • Journal of Chromatography B: Biomedical Sciences and Applications. 528:221–227.