Effect of P-Glycoprotein on the Pharmacokinetics and Tissue Distribution of Enaminone Anticonvulsants: Analysis by Population and Physiological Approaches

ABSTRACT Multidrug resistance (MDR), mediated by P-glycoprotein (Pgp) has been identified as altering the disposition of structurally diverse compounds. Previous in vitro studies in bovine brain microvascular endothelial cells and MCF/Adr [Adriamycin (doxorubicin)-resistant human breast cancer] cells displayed that the transport of enaminone anticonvulsants was influenced by Pgp. Therefore the objectives of this study was to further evaluate the influence of Pgp on the pharmacokinetics and tissue distribution of the enaminone analogs. mdr1ab (ϩ/ϩ) and mdr1ab (Ϫ/Ϫ) male mice (20 Ϯ 5 g) were administered DM5 (methyl 4-[(4Ј-chlorophenyl)amino]-6-methyl-2-oxo-3-cyclohexene-1-carboxylate) or DM44 (12.5 mg/kg, i.v.). Cohorts (n ϭ 3) were sacrificed over a 12-h period, and samples were analyzed by a validated UV-high performance liquid chromatography assay method. Population analysis was used to estimate pharmacokinetic parameters and partition coefficients were determined for tissues. The clearance (0.51 versus 0.33 l/h/kg) and V d (1.25 versus 0.93 l/kg) of DM5 were found to be higher (p Ͻ 0.05), however the area under the curve (26.1 versus 38.2 g/ml ⅐ h) was lower (p Ͻ 0.05) in mdr1a/1b (Ϫ/Ϫ) versus mdr1a/1b (ϩ/ϩ) mice, respectively. Similar findings were observed for DM44. Tissues known to express Pgp such as the heart, liver, lung, and brain displayed 2-fold or higher tissue levels in mdr1a/1b (Ϫ/Ϫ) versus mdr1a/1b (ϩ/ϩ) mice. These results strongly suggest that Pgp may influence enaminone tissue distribution and pharmacokinetics and may play a significant role in the effective treatment of epilepsy with these analogs

Methadone induces the expression of hepatic drug-metabolizing enzymes through the activation of pregnane X receptor and constitutive androstane receptor. Drug Metab. Dispos

ABSTRACT: Methadone (MD) is the most established substance abuse pharmacotherapy of choice for the management of heroin dependence. To date, drug-drug interactions involving MD have been characterized asymmetrically among existing reports, which describe how other drugs affect the metabolic or pharmacokinetic profiles of MD; however, limited information is available regarding the potential for MD to influence similar fates of coadministered drugs. Moreover, little to no mechanistic evidence has been explored. Here, we show that MD induces hepatic drug-metabolizing enzyme

Methadone induces the expression of hepatic drug-metabolizing enzymes through the activation of pregnane X receptor and constitutive androstane receptor. Drug Metab. Dispos

Abstract Methadone (MD) is the most established substance abuse pharmacotherapy of choice for the management of heroin dependence. To date, drug-drug interactions involving MD have been characterized asymmetrically among existing reports, which describe how other drugs affect the metabolic or pharmacokinetic profiles of MD, yet limited information is available regarding the potential for MD to influence similar fates of coadministered drugs. Moreover, little to no mechanistic evidence has been explored. Here, we demonstrate that MD induces hepatic drug-metabolizing enzymes (DMEs) through the activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR)

Investigation of the potential pharmacokinetic and pharmaco-dynamic drug interaction between AHN 1-055, a potent benztropine analog used for cocaine abuse, and cocaine after dosing rats using intracerebral microdialysis

Purpose. AHN 1-055, a benztropine (BZT) analog, binds with high affinity to the dopamine transporter (DAT), possesses behavioral, pharmacokinetic (PK) and brain microdialysate dopamine (DA) profiles distinct from cocaine. Accordingly, the objectives of this study were to evaluate the pharmacokinetics and dopamine release of AHN 1-055, in the presence of cocaine. Methods. Male Sprague Dawley rats (~300 g) were administered 5 mg/kg of AHN 1-055 and cocaine i.v. and blood and brain samples were collected over 36 h. In addition, dialysis probes were stereotaxically implanted into the nucleus accumbens and extracellular fluid (ECF) DA levels were measured. PK and PD models were used to describe the relationship between the AHN 1-055, cocaine and DA levels. Results. No significant (p50.05) differences were found in the PK parameters of AHN 1-055 alone (Vdss=18.7 l/kg, Cl=1.8 l/h/kg and t₁/₂=7.69 h) or AHN 1-055 with cocaine (Vdss=17.4 l/kg, Cl=1.9 l/h/kg and t₁/₂=6.82 h). The brain-to-plasma (B/P) ratios (B/PAHN ₁₋₀₅₅=4.8 vs B/Pwith cocaine=4.4) and half-lives (t₁/₂(AHN ₁₋₀₅₅)=6.2 h vs t₁/₂(cocaine)=5.6 h for AHN 1-055 alone and with cocaine were comparable. AHN 1-055 DA profiles were significantly different after co-administration with cocaine. There were no differences in the IC₅₀ for AHN 1-055, with cocaine, however, the IC₅₀ for cocaine was significantly reduced with AHN 1-055. Conclusions. The PK parameters of AHN 1-055 were not changed, however, the effect on DA levels was affected when cocaine was administered with AHNDA profile is affected when dosed with cocaine. This latter effect is a desirable attribute in the development of a medication as a potential substitute therapeutic medication for the treatment of cocaine abuse.12 page(s

Pharmacodynamic Assessment of the Benztropine Analogues AHN-1055 and AHN-2005 Using Intracerebral Microdialysis to Evaluate Brain Dopamine Levels and Pharmacokinetic/Pharmacodynamic Modeling

10 page(s