Relationship between hepatic cytochrome P450 3A content and activity and the disposition of midazolam administered orally.

It was recently shown by others that the clearance of midazolam/kg body weight after iv administration correlates with hepatic cytochrome P450 (CYP or P450) 3A content in liver transplant patients. However, after po administration midazolam undergoes significant first-pass metabolism, with significant intestinal extraction. The relationship between hepatic CYP3A and midazolam disposition after po administration had not previously been investigated. The aim of this study was to compare intraindividually hepatic CYP3A content and activity with the in vivo pharmacokinetics of midazolam (7.5 mg) administered po. For 15 patients scheduled for partial liver resection, the AUC values for the observed time period (AUC0-5hr) and to infinity (AUCinf) and the clearance were determined. In a macroscopically normal area of resected liver tissue, the microsomal CYP3A4 content (nanomoles per nanomole of total P450) was measured by immunoblot analysis and parameters (apparent Vmax, apparent KM, and intrinsic clearance) for the microsomal alpha-hydroxylation of midazolam were determined. Clearance/kg in vivo correlated with the apparent Vmax (r2 = 0.45, p < 0.01) and the CYP3A4 content (r2 = 0.29, p < 0.05). We conclude that interindividual variability in the pharmacokinetics of po administered midazolam is in part determined by interindividual variability in the hepatic microsomal Vmax for the alpha-hydroxylation of midazolam. However, the relationship between the disposition of midazolam administered po and hepatic CYP3A content is weaker than that reported after iv administration, indicating the importance of the contribution of intestinal CYP3A to the in vivo disposition of midazolam administered po.

[Secondary resistance to coumarin derivatives in a patient with a hypercoagulability syndrome]. / Sekundäre Resistenz gegen Cumarinderivate bei einer Patientin mit Hyperkoagulabilitäts-Syndrom.

HISTORY AND CLINICAL FINDINGS: A 23-year-old woman with deep (leg) vein thrombosis was hospitalised because the Quick value had not decreased despite administration of phenprocoumon. Two years previously she had sustained an anterior wall myocardial infarction and a scar on her right kidney had been an incidental sonographic finding. There was bluish, fine reticular discoloration over the toes of both legs. Physical examination was otherwise unremarkable except for obesity. INVESTIGATIONS: The concentration of creatine kinase was raised to 250 U/l and that of lactate dehydrogenase to 300 U/l. The platelet count was decreased to 75/nl. The level of IgG anti-cardiolipin antibodies was raised (204 U/l) and the test for lupus anticoagulant positive. A biopsy of the skin from a toe revealing livedoid vasculitis, primary antiphospholipid syndrome (PAPS) was diagnosed. TREATMENT AND COURSE: Noncompliance, excessive vitamin K ingestion, drug interaction and malabsorption were excluded as cause of the lacking action of phenprocoumon. Despite anti-coagulation with high-dosage low-molecular heparin and inhibition of platelet aggregation with ticlopidine and finally also immunosuppressive treatment with cyclophosphamide, skin necroses developed on the toes and she had recurrent pulmonary embolisms of which she died. CONCLUSION: Standard treatment of PAPS is effective anti-coagulation with coumarin derivatives. Secondary resistance to coumarin is a rare occurrence: its cause remains unknown.

[Treatment in a heparin-induced skin reaction with a low-molecular heparin analog]. / Behandlung bei heparin-induzierter kutaner Reaktion mit einem niedermolekularen Heparin-Analog.

Deep vein thrombosis in the leg and pelvis was seen in a 26-year old woman during the seventh month of pregnancy. 20 days after initial administration of heparin sodium, a local, markedly progressing erythema and induration was observed at the subcutaneous injection sites. The same cutaneous reactions occurred after application of heparin calcium. Following oral anticoagulation treatment with phenprocoumon, the patient was treated towards the end of pregnancy and directly post partum with a low-molecular semisynthetic heparin analogue without any side effects. The skin test again showed good tolerance of another heparin analogue and a low-molecular heparin.

[Comparative study of the effect of famotidine and cimetidine on antipyrine pharmacokinetics in the human]. / Vergleichende Untersuchungen über den Einfluss von Famotidin und Cimetidin auf die Antipyrin-Pharmakokinetik beim Menschen.

In a randomized order the pharmacokinetics of antipyrine were studied following a 5 days treatment period with placebo, 1000 mg cimetidine and 40 mg famotidine daily, respectively in 7 healthy volunteers. In contrast to cimetidine, famotidine did not significantly affect the disposition of antipyrine in these subjects. Famotidine like the other guanidino-thiazole containing compound tiotidine appears to be free from this unwanted effect on drug metabolism in the liver.