Telaprevir has very poor penetration of the blood brain

by Selleckchem | Nov 15 2012

The principal metabolic fate of loperamide in humans involves oxidative N dealkylation to N demethyl loperamide as the principal metabolite. In human liver microsomes, cytochrome P450 3A4 appears to be the major isozyme responsible for loperamide metabolism, with minor contributions from CYP2B6. At the doses used to control diarrhea, LOP has very poor penetration of the blood brain barrier and produces no central opioid effects, such as respiratory Telaprevir depression, pupillary constrictions, analgesia, or changes in alertness. The poor central nervous system penetration is attributed both to LOP active cellular efflux via the multidrug resistance transporter P glycoprotein in the blood brain barrier and to low systemic oral bioavailability.
When P gp is VX-770 inhibited,LOP and its metabolites may potentially enter the brain and cause opioid induced central neurological adverse events . Current treatment for human immunodeficiency virus type 1 infection consists of Dasatinib a combination of antiretroviral agents of different classes. Tipranavir is a potent nonpeptidic HIV 1 and HIV 2 protease inhibitor that is active against laboratory strains and clinical isolates of HIV 1 that are broadly resistant to peptidic PIs and is used for therapy of treatment experienced patients who are infected with HIV 1. In addition to antiretroviral agents, patients are often concomitantly treated for opportunistic infections and comorbidities or to control side effects. As with other PIs, the most frequent side effect of TPV is diarrhea, which may be treated with LOP.

Tipranavir is a substrate for and an inducer of hepatic CYP3A and may also be a substrate for P gp. On the other hand, ritonavir inhibits hepatic and, possibly gastrointestinal CYP3A, thereby potentially altering the systemic bioavailability of PIs like TPV metabolized by this enzyme. Because of this metabolic inhibition, RTV is often used to boost and maintain plasma concentrations of coadministered PIs, such as TPV. RTV is a substrate for P gp and also a possible inhibitor of P gp. If it is an inhibitor of P gp, RTV may decrease the efflux of LOP out of the CNS, thereby increasing the CNS concentration and central opiate effects of LOP. On the other hand, if RTV Raltegravir inhibits only CYP3A, which would produce higher concentrations of LOP with concurrent decreases of the LOP metabolite, the concurrent use of LOP and RTV would be devoid of CNS activity.
Because there is the potential for the use of RTV boosted TPV together with LOP, all three of which are substrates for P gp, this study assessed the pharmacodynamic and pharmacokinetic interactions of LOP with TPV, RTV, and the Vorinostat combination TPV RTV in HIV 1 negative, healthy adults. The respiratory response to LOP alone and after administration of TPV, RTV, and TPV RTV were the primary end points in this study. A secondary pharmacodynamic end point was the pupillary response to LOP after administration of TPV, RTV, or TPV RTV, as measured by the ratio between the diameter of the pupil and the diameter of the iris.