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Biomedical subjects

H Kraul

Publications and source records attributed to H Kraul.

15 recordsLinked to original sources
PubMed1994

Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects.

The objective of the presented two-way randomized crossover study was to investigate whether repeated doses of grapefruit juice (200 ml at 0, 2, 4, 8 and 12 h) enhanced bioavailability of diltiazem (120 mg, orally) in nine healthy male subjects. Grapefruit juice did not alter AUC or cmax of diltiazem, whereas the half life experienced a slight, but statistically significant, increase (4.1 +/- = 1.2 vs 5.1 +/- 0.7 h). The N-demethyldiltiazem/diltiazem and deacetyldiltiazem/diltiazem ratios were not affected by grapefruit juice intake, which indicates that these metabolic pathways are not inhibited. Whereas bioavailability of some calcium channel antagonists of the dihydropyridine type metabolized via the same cytochrome P450 has been shown to be dramatically increased by grapefruit juice intake, the bioavailability of the benzothiazepine calcium channel antagonist diltiazem remained unchanged. This suggests that factors other than biotransformation may contribute to the clear effect of grapefruit juice on the bioavailability of those substances.

Adult↗
PubMed1992

Interindividual variability of coumarin 7-hydroxylation in healthy volunteers.

A test designed to estimate the extent and rate of formation of 7-hydroxycoumarin by measuring the urinary excretion of the metabolite in humans after administering 5 mg coumarin was developed. Coumarin was rapidly metabolized after oral administration and more than 95% of the 7OHC formed was excreted in 4 h. The total amount of 7OHC formed was 64 +/- 15% (mean +/- SD, variation 20-100%) of the dose given. The percentage of 7OHC excreted in 2 h, as compared with the 7OHC excretion in 4 h, was found to be a constant and stable individual characteristic for the rate of the formation of 7OHC ('2 h coumarin test'). In 110 volunteers, there was a great interindividual variability in the extent and rate of 7OHC formation. Four individuals had relatively 'slow' coumarin test values (50-60%), but much larger populations would be needed for the demonstration of polymorphism.

Adult↗
PubMed1992

Lack of effect of diacetyl-splenopentin (Berlopentin) on the pharmacokinetics of caffeine.

The influence of Berlopentin on caffeine clearance was measured after a 6 week i.v. treatment or a 4 week s.c. administration within a phase I trial. It was demonstrated that therapy with Berlopentin did not affect significantly caffeine elimination. Thus, clearance of drugs which are biotransformed by hepatic microsomal oxidation are unlikely to be affected by the coadministration of Berlopentin.

Adult↗
PubMed1991

Comparison of in vitro and in vivo biotransformation in patients with liver disease of differing severity.

The activity of 7-ethoxycoumarin O-deethylase (ECOD) has been measured in liver biopsy samples from 23 patients (smokers and non-smokers) with different degrees of structural liver damage. The results, which reflect in vitro cytochrome P450-dependent biotransformation, were correlated with various measures of the P450-dependent in vivo elimination of caffeine and metamizol. The relatively non-specific, low affinity component of ECOD activity was significantly correlated with the kinetics of metamizol (mean residence time, apparent clearance, half-life, area under the concentration-time curve, and metabolite excretion in the urine). Thus, metamizol elimination, which is mainly due to P450 IIB, and the low affinity component of ECOD both reflect, at least in part, the activity of the same form of P450. In contrast, caffeine biotransformation, which is via P450 IA, was not correlated with ECOD activity. There was no relation between the kinetics of metamizol and caffeine, perhaps because of the inducing effect that smoking has on caffeine elimination. In patients with liver disease, smoking appears to alter the elimination of caffeine more than the degree of liver disease.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1991

The cerium-induced liver injury and oxidative drug metabolism in DBA/2 and C57BL/6 mice.

The influence of the known hepatotoxic agent, cerium (Ce) on the activity of liver microsomal monoxygenases, especially coumarin 7-hydroxylase (COH) was investigated in two inbred strains of male mice, DBA/2N and C57BL/6N. Ce was injected intravenously in three doses (0.5, 1.0 and 2.0 mg/kg body wt) and the animals were killed 24 or 72 h later. On the basis of histological assessment of the liver, C57BL/6N mice are apparently more resistant to the hepatotoxic effect of Ce. At 24 h, COH activity was increased in a dose-dependent manner in DBA/2 animals, whereas no change was seen in C57BL/6N animals. A significant increase in all other enzymes studied, cytochrome P-450 (P450), ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase, was seen in DBA/2 mice injected with the highest dose of Ce. At 72 h Ce increased CON activity, as well as other enzymes, in C57BL/6N mice in a dose-dependent manner, whereas in DBA/2 mice the increase was only seen after the two lower doses, the highest dose causing severe morphological changes in the liver structure and a clear decrease in COH and other activities. The distribution studies with Ce-141 showed that C57BL/6N livers contained more Ce than DBA/2 livers after the highest dose.

Animals↗
PubMed1991

Nephrotoxic effects of diethylene glycol (DEG) in rats.

Diethylene glycol (DEG) is a widely used substance with various risks of intoxication. In adult rats influences of DEG on functional parameters are characterized, indicating early signs of nephrotoxicity. A dose dependent proteinuria, an oliguric effect, an increased excretion of free hydrogen ions and a compensated impairment of renal tubular transport processes can be stated (0.25, 0.5 and 0.75 ml DEG/100 g b.m. i.p.). Following a single dose of 0.5 ml DEG/100 g b.m. i.p. the maximally expressed nephrotoxic effect is measurable 4 to 8 days after administration.

Animals↗
PubMed1991

[7-ethoxycoumarin o-deethylase and fibrosis in chronic liver diseases].

In the liver biopsy of 100 patients with chronic liver diseases, the activity of 7-ethoxycoumarin O-deethylase (ECOD) was determined as a parameter of hepatic monooxygenase system and was compared with some markers of fibrosis e.g. collagen peptidase and hydroxyproline. ECOD was significantly different in healthy liver, fatty liver, chronic active hepatitis (CAH) and cirrhosis. The importance of the fibrotic process was shown by the significant correlations between ECOD and the signs of fibrosis in the liver biopsy. A connection between ECOD and the markers of fibrosis was not found. Further research is necessary to clarify this difference.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1991

[Comparison of ICG elimination with biotransformation of model substances and histological features of liver biopsy in liver diseases].

The elimination of indocyanine green (ICG) was measured in 45 patients with histologically proved liver disease to evaluate liver blood flow. Furthermore, the elimination of caffeine and metamizol was determined in serum as a parameter of in vivo biotransformation. In a further step the activity of 7-ethoxycoumarin O-deethylation was measured in liver biopsy samples of 30 out of 45 patients (in vitro parameter of biotransformation). The half-life of ICG was compared with the data of biotransformation by means of the calculation of correlations with special consideration of histological findings in liver biopsy samples (monocellular necrosis, intra-acinar fibrosis, structural transformation). Results demonstrate that ICG-elimination is a nonsufficient criterion of liver blood flow in patients with liver disease, because of considerable variation and many influencing factors including the function of the liver cells. Therefore, it is difficult to evaluate results.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1990

[Simultaneous administration of various model substances for characterizing in vivo biotransformation in chronic liver diseases].

16 patients with different chronic liver diseases were given single doses of the model substances caffeine, metamizol, sufamethacine and debrisoquine. This was followed by the simultaneous administration of all these substances as a "cocktail". A comparison between the single and the "cocktail" dosage did not reveal any significant differences in the pharmacokinetic parameters. So the "cocktail" administration is even possible in chronic liver diseases. Requiring relatively little time, it makes statements possible concerning various cytochrome P450 enzymes including the types of hydroxylation and acetylation. Intraindividual variations can be ruled out.

Biotransformation↗
PubMed1990

[Effect of 3 months of thioacetamide treatment on liver biotransformation in vivo and in vitro (various times after discontinuation)].

Female Uje: WIST rats received thioacetamide (TAA) in the tap water (0.3 g/l) from the 4th to 6th months of life to produce experimental liver cirrhosis. Immediately, 2 and 7 days after TAA cessation it was investigated by means of in vivo (caffeine and metamizol elimination) and vitro methods (cytochrome P-450, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylation), whether this animal model represents the restricted cytochrome P-450-dependent biotransformation comparable to human liver cirrhosis. The total capacity of the liver was diminished immediately and 2 days after TAA cessation. After 7 days the capacity was unchanged compared to the controls or partly even enhanced. Therefore, this animal model reflects rather a short time than a stable alteration of biotransformation after TAA cessation comparable to human liver cirrhosis.

Animals↗
PubMed1989

Cytochrome P-450-dependent biotransformation in Uje:WIST rats with chronic liver injury induced by thioacetamide.

In female Uje:WIST rats micronodular liver cirrhosis was produced by thioacetamide (TAA) given in the drinking water (0.3 g/l) from the 4th to 6th months of life. 14 d after TAA cessation it was examined, whether this animal model reflects the restricted cytochrome P-450-dependent biotransformation in severe stages of human liver cirrhosis by in vivo (caffeine and metamizol elimination) and in vitro methods (cytochrome P-450, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylation, ethylmorphine N-demethylation). The total biotransformation capacity was unchanged in TAA rats, partly even enhanced. Only several in vitro parameters reflect diminished cytochrome P-450-dependent biotransformation calculated per weight unit comparable to severe stages of human liver cirrhosis. Therefore, the chosen experimental conditions are suitable for conclusions concerning cytochrome P-450-dependent biotransformation in early rather than in severe stages of human liver cirrhosis.

Aminopyrine↗
PubMed1989

Studies on the in-vitro biotransformation in patients with liver diseases.

The activity of 7-ethoxycoumarin O-deethylase (ECOD) was determined in the human liver bioptate of 53 patients with chronic liver diseases. Remarkable are the lower values of ECOD in the hepatoses, chronic hepatitis and cirrhosis as compared to patients with normal histology or residual hepatitis. The decline in the activity of ECOD in the patients with chronic hepatitis and cirrhosis has to be seen in connection with parenchymatous necrosis, nodular liver transformation and intracinar fibrosis. For the time being it is not possible to give a satisfactory explanation of the decrease in the ECOD activity of the hepatoses.

7-Alkoxycoumarin O-Dealkylase↗