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  • 1
    Digitale Medien
    Digitale Medien
    On the intraindividual variability and chronobiology of cyclosporine pharmacokinetics in renal transplantation (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 265-269 
    Details
    ISSN: 1432-1041
    Schlagwort(e): Cyclosporine ; Renal transplantation ; pharmacokinetics ; intraindividual variation ; circadian variation
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period. The absolute percentage intraindividual difference in daytime AUC (0–12 h) ranged from 2% to 54% (mean 30%), and the corresponding variability in nighttime AUC (0–12 h) ranged from 5% to 80% (mean 34%). The pharmacokinetic variables t1/2, tmax and Cmax were more variable than the AUC (0–12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng · ml−1 versus 223 ng · ml−1. This, together with a significantly longer t1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA. In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime. It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00271369
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  • 2
    Digitale Medien
    Digitale Medien
    The effect of codeine on gastrointestinal transit in extensive and poor metabolisers of debrisoquine (1997)
    Springer
    European journal of clinical pharmacology 53 (1997), S. 145-148 
    Details
    ISSN: 1432-1041
    Schlagwort(e): Key words Codeine ; Gastrointestinal transit ; pharmacogenetic ; debrisoquine hydroxylation phenotype
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract Methods: Codeine (50 mg) was administered to 12 extensive metabolisers (EM) and 12 poor metabolisers (PM) of debrisoquine. The oro-caecal transit time was estimated by the hydrogen breath test. The urinary excretion of codeine and metabolites during a 6-h interval was estimated after simultaneous analysis of codeine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), morphine (M), normorphine (NM), norcodeine, norcodeine glucuronide and codeine-6-glucuronide using HPLC. Results: The mean transit times after placebo were 1.3 h in the EM and 1.4 h in the PM. The corresponding figures after ingestion of codeine were 2.2 h and 2.1 h. The differences between the groups were statistically and clinically insignificant. The effect of codeine compared with placebo was significantly different in both groups. As expected, the metabolites of the O-demethylation pathway, M, M6G, M3G and NM were significantly lower in the PM. Interestingly, the recovery of the dose in the form of codeine (〉1.7 times) and norcodeine (〉2.5 times) was significantly higher in the PM, indicating compensatory metabolism via N-demethylation. Conclusion: In contrast to the analgesic effect, the prolongation of gastrointestinal transit caused by the drug does not depend on the formation of O-demethylated active metabolites M, M6G or NM.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s002280050353
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  • 3
    Digitale Medien
    Digitale Medien
    Effect of codeine on oro-cecal transit time in Chinese healthy volunteers in comparison with Caucasian subjects (1999)
    Springer
    European journal of clinical pharmacology 54 (1999), S. 839-842 
    Details
    ISSN: 1432-1041
    Schlagwort(e): Key words Codeine ; Oro-cecal transit time ; Lactulose hydrogen breath test
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract Objectives: To evaluate the effect of codeine on oro-cecal transit time (OCTT) in Chinese subjects. Methods: OCTT was measured with the hydrogen breath test in 12 Chinese healthy volunteers on two occasions: after placebo and after a single oral dose of codeine 50 mg. Codeine and its metabolites in urine were measured by HPLC. The Results of this study were compared with those previously obtained from Caucasian subjects. Results and conclusion: The mean OCTT increased significantly after a single oral dose of codeine 50 mg [2.6 (1.2) h] compared with placebo [1.9 (0.6) h] in the Chinese subjects (P = 0.05). The increase in OCTT after codeine was similar in the Caucasian [0.9 (0.8) h] and in the Chinese subjects [0.7 (0.9) h]. However, the Chinese subjects had a significantly longer OCTT after placebo [1.9 (0.6) h] compared with the Caucasian subjects [1.3 (0.6) h, P 〈 0.05], possibly due to different environmental factors.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s002280050563
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  • 4
    Digitale Medien
    Digitale Medien
    Kinetics of morphine in patients with renal failure (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 377-382 
    Details
    ISSN: 1432-1041
    Schlagwort(e): morphine ; renal failure ; pharmacokinetics ; morphine-3-glucuronide
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The kinetics of morphine and its glucuronidated metabolites were investigated in seven patients with advanced renal failure. The terminal elimination half life of morphine varied between 1.5 and 4.0 h (mean 2.4 h), the volume of distribution between 2.5 and 6.3 l·kg−1 (mean 4.4 l·kg−1) and the total plasma clearance between 13.3 and 31.3 l·min−1·kg−1 (mean 21.1 l·kg−1). There were no statistically significant differences between the pharmacokinetic data in the uraemic patients and in a control group of cancer patients with normal kidney function. The concentrations of the glucuronidated metabolites rapidly rose to levels above those of morphine. The elimination half-life of M3G varied between 14.5 and 118.8 h (mean 49.6 h) in the renal failure patients, which is distinctly different from the 2.4 to 6.7 h (mean 4.0 h) found in patients with normal kidney function. There was a significant correlation between the half-life of M3G and renal function estimated as serum urea. Thus, the metabolism of morphine in patients with kidney disease is not significantly impaired. The clinical importance of the high concentrations of glucuronides in uraemic patients is not known.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00543973
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  • 5
    Digitale Medien
    Digitale Medien
    Morphine glucuronidation in human fetal and adult liver (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 553-558 
    Details
    ISSN: 1432-1041
    Schlagwort(e): glucuronidation ; morphine ; UDP-glucuronyltransferase ; adult liver ; fetal liver ; enzyme heterogeneity
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The glucuronyltransferase activity towards morphine was measured in microsomes isolated from liver specimens obtained from human fetuses and cancer patients. All the fetal livers investigated had measurable UDP-glucuronyltransferase activity towards morphine. There was no correlation between the gestational age (15 to 27 weeks) and the glucuronidation rate. The mean value of the enzymatic activities was higher in fetal livers obtained by hysterotomy (0.20 nmoles×min−1×mg−1) than in livers obtained after induced abortion (0.11 nmoles×min−1×mg−1). The average rate of glucuronidation in microsomes from adult liver (mean 1.15 nmoles×mint-1×mg−1) was 6 to 10 times higher than in the fetal liver microsomes. Together with previous investigations on human adult and fetal liver glucuronidation, the present results support the theory of heterogeneity of human UDP-glucuronyltransferase.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00609630
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  • 6
    Digitale Medien
    Digitale Medien
    Steady-state kinetics and analgesic effect of oral morphine in cancer patients (1983)
    Springer
    European journal of clinical pharmacology 24 (1983), S. 537-542 
    Details
    ISSN: 1432-1041
    Schlagwort(e): morphine ; analgesic activity ; tablets solution ; pharmacokinetics ; bioavailability ; pain score ; dose-response relationship ; chronic pain
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The steady-state kinetics of morphine given as tablets and solution were compared in 7 cancer patients with chronic pain. There was no accumulation of morphine (20–40 mg) when repeatedly administered every 4 to 6 h. The mean steady-state concentration of morphine during the dose interval varied between 5.9 and 68.4 ng/ml (20.7–240 nmol/l), and was linearly related to the daily dose of morphine. There were no significant differences between the tablets and the solution of morphine with regard to relative oral bioavailability or peak concentration. The time-to-maximum plasma concentrations was significantly longer for the tablets. The pain score profile, assessed by a visual analogue scale during a dose interval, showed a similar pattern after the two oral formulations of morphine. No significant linear relationship between the scores and the plasma concentrations of morphine was observed.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00609900
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  • 7
    Digitale Medien
    Digitale Medien
    Different effects of inhibitors on the O - and N -demethylation of codeine in human liver microsomes (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 41-47 
    Details
    ISSN: 1432-1041
    Schlagwort(e): Key words Codeine ;  O-demethylation ;  N-demethylation; human liver microsomes
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Abstract Objective: The O- and N-demethylation of codeine is catalysed by CYP2D6 and CYP3A4 respectively. The formation rates of morphine by O-demethylation and norcodeine by N-demethylation were studied in two sets of human liver microsomes. Results: Relatively high K m values were found for both O- and N-demethylations, suggesting a low affinity to the corresponding enzymes. The inhibitory effects of various drugs were found to be different for O- and N-demethylations. The substrates of CYP2D6 such as thioridazine, amitriptyline and metoprolol inhibited the O-demethylation of codeine preferentially, while the substrates of CYP3A4 such as cyclosporine A, midazolam and erythromycin were all strong inhibitors of the N-demethylation of codeine. Quinidine and lignocaine, although they are substrates of CYP3A, showed preferential inhibition over the O-demethylation of codeine, suggesting a low affinity to the CYP3A. Methadone and dextropropoxyphene showed a preferential inhibition of CYP2D6 over CYP3A, while theophylline did not inhibit the O- or N-demethylation to a greater extent. Conclusion: It seems that there was a good correspondence between the capacity of drugs to inhibit the O- and N-demethylation of codeine in human liver microsomes and their apparent metabolism by CYP2D6 or CYP3A4, respectively in vivo in man, suggesting that this in vitro inhibition test may be a useful screen for drugs which interact with these two important drug-metabolising enzymes.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s002280050247
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  • 8
    Digitale Medien
    Digitale Medien
    Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 553-556 
    Details
    ISSN: 1432-1041
    Schlagwort(e): Genetic polymorphism ; Cytochrome P450 ; drug metabolism ; codeine ; interethnic differences ; Chinese ; debrisoquine
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The Far Eastern and Caucasian populations are strikingly different with respect to the debrisoquine/sparteine hydroxylation polymorphism. The number of poor metabolizers, as defined for Caucasians, is very low among Chinese and Japanese. We investigated the molecular basis for this difference by analysis of the CYP2D6 gene in 115 Chinese subjects, combined with phenotypic classification of codeine and debrisoquine metabolism. A correlation between the rates of metabolism of these two drugs and genotype, as analyzed by RFLP using XbaI, was observed among the Chinese. A high frequency (37%) of alleles indicative of gene insertions (reflected by Xba I 44kb fragments) was recorded in the Chinese, but was not associated with the poor metabolizer phenotype, as it is in Caucasians. PCR amplification of part of the CYP2D6 gene with mutation specific primers for CYP2D6A (29A) and CYP2D6B (29B) allelic variants revealed that the XbaI 44kb fragment in Chinese apparently contains a functional CYP2D6 gene, in contrast to the situation among Caucasians. The results provide a molecular explanation of the interethnic difference in the metabolism of drugs affected by the debrisoquine hydroxylation polymorphism.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00279968
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  • 9
    Digitale Medien
    Digitale Medien
    Single-dose and steady-state kinetics of morphine and its metabolites in cancer patients — a comparison of two oral formulations (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 585-591 
    Details
    ISSN: 1432-1041
    Schlagwort(e): Morphine ; metabolites ; clinical trial ; pharmacokinetics ; controlled release formulation ; cancer patients ; adverse effects
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The single-dose and steady state kinetics of morphine given as controlled-release tablets (30 mg every 12 h) and as a solution (15 mg every 6 h) have been compared in 11 cancer patients with chronic pain. The concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were analyzed by HPLC. There were no significant differences between the tablets and solution in the mean steady state concentrations of morphine, M3G or M6G. The tmax was 3.3 h for the tablets compared to 1.1 h for the solution. After giving the controlled-release tablets every 12 h there was a significantly higher fluctuation index of the morphine concentrations than after the solution. Urinary recovery at steady state was comparable between the two preparations, with averages of 57% and 47%, respectively. Thus, no major differences were found in the pharmacokinetics of morphine and its glucuronidated metabolites after 30 mg morphine as controlled-release tablets every 12 h or 15 mg of morphine solution every 6 h, except for a significantly longer tmax and greater fluctuation in morphine concentrations after the controlled-release tablets.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00279975
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