Summary:Busulphan and cyclophosphamide (Bu/CP) are widely used in preparative regimens for bone marrow transplantation. Many studies have shown a wide variation in busulphan pharmacokinetics. Moreover, higher rates of liver toxicity were reported in Bu/CP protocols than in a total body irradiation (TBI)-containing regimen. In the present paper we investigated the effect of the time interval between the last dose of busulphan and the first dose of cyclophosphamide on the pharmacokinetics of CP and its cytotoxic metabolite 4-hydroperoxycyclophosphamide (4-OHCP). Thirty-six patients undergoing bone marrow transplantation (BMT) were included in the study. We also investigated the occurrence of venoocclusive disease, mucositis and graft-versus-host disease. Ten patients conditioned with CP followed by TBI served as a control group (TBI). Twenty-six patients were conditioned with Bu/CP. The patients received Bu
We studied the pharmacokinetics after caudal block of ropivacaine (2 mg ml-1, 1 ml kg-1) performed in 20 children aged 1-8 yr undergoing subumbilical surgery, in this open, non-comparative, multicentre study. Venous blood samples were collected up to 12-36 h. The mean (SD) peak plasma concentration, 0.47 (0.16) mg litre-1, was achieved after 12-249 min. The free fraction was 5% and the highest individual peak plasma concentration of free ropivacaine was 0.04 mg litre-1. Clearance was 7.4 (1.9) ml min-1 kg-1 and the terminal half-life 3.2 (0.8) h. Thus, the free plasma concentrations of ropivacaine were well below those associated with toxic symptoms in adults and the capacity to eliminate ropivacaine seems to be well developed in this age group. In this open study of 20 patients, ropivacaine was well tolerated and provided satisfactory postoperative pain relief without observable motor block.
The presented mechanism-based enzyme induction model where the pharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated.
CYP1A2 is the most important isozyme for the metabolism of ropivacaine. Drug-drug interactions with strong inhibitors of this isozyme could be of clinical relevance during repeated administration. A potent inhibitor of CYP3A4 causes a minor decrease in clearance, which should be of no clinical relevance.
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