three Drug interactions that involve many different mechanisms To assess the CNS distribution of cyclophosphamide and ifosfamide, Yule et al evaluated the plasma and CSF concentrations of these medication in 25 pediatric oncology patients. Subjects received cyclophosphamide or continuous infusion of ifosfamide over 72 hours. 7 Individuals who were treated with cyclophosphamide for non Hodgkin’s lymphoma had substantially greater cyclophosphamide CSF concentrations, compared with 13 patients that had been treated for acute lynphoblastic leukemia. The CSF toplasma concentration ratio of cyclophosphamide was three fold better in lymphoma than in leukemia individuals. The authors suggested the variations could result from tightening on the BBB by co administration of dexamethasone to the therapy of acute lymphoblastic leukemia. Similarly, 1 patient that received dexamethasone had the lowest CSF to plasma concentration ratio of ifosfamide.
Because dexamethasone decreases BBB permeability by many mechanisms , it could lead to DDIs with respect to drug distribution in to the CNS. The clinical significance of this mechanism of DDI is simply not clear. three Drug interactions that involve blood brain barrier tight junctions CSF concentrations have also been utilized to assess the impact of osmotic BBBD on CNS penetration hif 1 inhibitors of methotrexate. As an example, intra arterial administration of methotrexate with osmotic BBBD resulted in as much as 6 fold enhancement of methotrexate CSF penetration, in comparison to intravenous or intra arterially administration . In general, osmotic BBBD enhanced clinical outcomes of cancer chemotherapy in phase I and phase II research , but hasn’t been evaluated in greater clinical trials. At this time, worries even now exist regarding efficacy and toxicity of osmotic BBBD.
1st, whereas osmotic BBBD possibly increases the distribution of hydrophilic compounds to the ISF, it could not improve their distribution in to the tumor itself, given the abnormalities of tumor microvessels. 2nd, non specific BBB disruption can augment neurotoxicity chloroxine with the chemotherapeutic compounds at the same time as that of many other substances that typically would not get accessibility into brain parenchyma . Additional selective opening of tumor blood barrier working with bradykinin analogues is studied in pediatric individuals with brain tumors, but did not improve the efficacy of carboplatin in these sufferers . At current, clinical studies on BBBD to enhance CNS drug delivery are ongoing, however the utilization of this process is restricted to one or two centers and this kind of DDI is not anticipated to arise using the utilization of traditional therapeutic regimens three.
Transporter mediated drug interactions Seeing that the discovery the calcium channel blocker verapamil can restore drug sensitivity in tumor cell lines , lots of agents are already investigated for their ability to inhibit P gp and hence reverse the multidrug resistance of tumors .