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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 277 (1973), S. 39-52 
    ISSN: 1432-1912
    Keywords: Cytochrome P-450 ; Metyrapone ; Active Centers of Enzyme ; Induction ; Enzyme Inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Metyrapone inhibits the N-demethylation of aminopyrine and ethylmorphine in rat liver microsomes non-competitively with concentrations in the micromolar range, and competitively in the range of 10−4 M. In the case of non-competitive inhibition, enzyme and inhibitor are present in similar amounts (“mutual depletion system”). Under these conditions Lineweaver-Burk kinetics do not apply, since the portion of inhibitor bound to the enzyme cannot be neglected. Inhibition of microsomal N-demethylating activity by increasing amounts of metyrapone and application of equations required for a mutual depletion system enable us to determine the following kinetic parameters: (1) the concentration of catalytically active and metyrapone sensitive centers (E t ) of cytochrome P-450, (2) their turnover number (TN), and (3) the true dissociation constant of the enzyme inhibitor complex, K i .—With aminopyrine as substrate and microsomes from phenobarbital (PB) pretreated rats, 1 mg of protein contains 4.7 nmoles of E t , i.e. about 2.2 catalytically active sites per molecule of cytochrome P-450; TN=3.4 min−1, and K i =2.2·10−6 M. The corresponding values for ethylmorphine and control rats are: E t =3.1 nmolles per mg of protein (4.4 sites per molecule), TN=1.94 min−1; K i =2.37·10−6M. PB-pretreated rats: E t =7.3 nmoles per mg of protein (3.5 sites per molecule) TN=2.0 min−1; K i =2.3·10−6 M. Comparing the values obtained for PB-pretreated rats and controls reveals that K i and TN remain constant but E t rises 2.3 fold. This is regarded to mean that PB pretreatment influences ethylmorphine N-demethylation only quantitatively but not qualitatively. The experiments described here provide data which improve the characterization of cytochrome P-450. They are derived from the overall rate of N-demethylation reactions in microsomes, independently from conventional spectrophotometric methods.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 277 (1973), S. 27-38 
    ISSN: 1432-1912
    Keywords: Cytochrome P-450 ; Metyrapone ; Liver Microsomes ; Enzyme Inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary N-demethylation of aminopyrine and ethylmorphine via hepatic microsomal mixed function oxidase cytochrome P-450 from rat is inhibited by metyrapone by two mechanisms: Non-competitive inhibition occurs at low concentrations (K i about 2·10−6 M); competitive inhibition is obtained at high concentrations (K i about 1·10−4 M). Lineweaver-Burk kinetics allow to determine the K i for inhibition at high concentrations. The K i for inhibition with low concentrations has been obtained by extrapolation. The inhibitor concentrations which yield 50% inhibition have been plotted versus v max at different protein dilutions. From these data it is strongly suggested that metyrapone is bound with different affinity at two binding sites of cytochrome P-450: One probably sharing with O2 and the other sharing with substrates, as proposed by Sweat et al. (1969) and Netter et al. (1969).
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Intensive care medicine 16 (1990), S. 448-453 
    ISSN: 1432-1238
    Keywords: Ceftriaxone ; Pharmacokinetics ; Acute renal failure ; Intensive care patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Serum concentrations of ceftriaxone (RocephinTM), a third generation cephalosporin, were monitored in 5 operative intensive care patients suffering from acute renal failure (ARF) and compared to those of 7 patients without renal disturbance. For a period of 7 days, a fixed dose of 2 g/day was given by a 15 min infusion. Pharmacokinetic parameters were calculated by fitting all serum and urine data measured over the period of treatment. Ceftriaxone free fraction was measured on days 2 and 7. There was no evidence for an intraindividual change in ceftriaxone-clearance during the observation period. Ceftriaxone renal clearance was closely dependent on creatinine clearance according to a linear regression expressed by Clren=0.14 Clcrea+2.2 (r=0.951,p〈0.0001). Total clearance was also associated with creatinine clearance: Cltot=0.19 Clcrea+8.2 (r=0.964,p〈0.0001). Related to the free fraction, renal clearance was in the range of the glomerular filtration rate. Non-renal clearance was strongly decreased when related to the free fraction indicating that biliary excretion is also impaired in patients with acute renal failure. Obviously no compensatory increase in hepatic ceftriaxone clearance takes place. It is concluded that elimination of ceftriaxone may be strongly impaired during acute renal failure in surgical intensive care patients and that dosage should be restricted according to degree of the impairment of creatinine clearance.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 45 (1993), S. 445-450 
    ISSN: 1432-1041
    Keywords: Metamizol ; Acute renal failure ; Sepsis ; intensive care patients ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the clearance of monomethylaminoantipyrine (MMAAP), the pharmacologically active form of metamizol, in 46 patients in surgical intensive care with different degrees of renal dysfunction. In 23 patients without any renal impairment, mean clearance was 2.8 ml·min−1·kg−1. Twentyone patients with acute renal impairment had a significantly reduced clearance of MMAAP (0.83 ml·min−1·kg−1). There was also reduced clearance in four patients with septic shock (1.0 ml·min−1·kg−1). Kinetics of the metabolites of MMAAP (N-formylaminoantipyrine (FAAP), aminoantipyrine (AAP), and its secondary product N-acetylaminoantipyrine (AcAAP)) were calculated. FAAP and AcAAP showed delayed invasion, which can be explained by reduced hepatic metabolic activity. The product of N-demethylation, AAP, was not significantly altered. The delayed elimination of monomethylaminoantipyrine can be explained by reduced hepatic function in parallel with acute renal failure due to disturbed cardiovascular function caused by septic shock. This may also lead to disturbed hepatic macro- and microperfusion associated with altered oxygen supply and oxygen consumption.
    Type of Medium: Electronic Resource
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