Drug metabolism and disposition : the biological fate of chemicals
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Drug Metab. Dispos. · Aug 2014
Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases.
Brain metastases are a major cause of mortality in patients with advanced melanoma. Adequate brain distribution of targeted agents for melanoma will be critical for treatment success. Recently, improvement in overall survival led to US Food and Drug Administration (FDA) approval of the v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, vemurafenib and dabrafenib, and the mitogen-activated protein kinase kinase-1 (MEK)-1/2 inhibitor, trametinib. ⋯ The brain-to-plasma partition coefficient (AUCbrain/AUCplasma) was approximately 5-fold higher in Mdr1a/b((-/-)) (P-gp knockout) and Mdr1a/b((-/-))Bcrp1((-/-)) (triple knockout) mice when compared with wild-type and Bcrp1((-/-)) (Bcrp knockout) mice. The brain distribution of trametinib was similar between the wild-type and Bcrp knockout mice. These results show that P-gp plays an important role in limiting brain distribution of trametinib and may have important implications for use of trametinib as single agent or in combination therapy for treatment of melanoma brain metastases.
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Bedaquiline is a recently approved drug for the treatment of multidrug-resistant tuberculosis. Adverse cardiac and hepatic drug reactions to bedaquiline have been noted in clinical practice. The current study investigated bedaquiline metabolism in human hepatocytes using a metabolomic approach. ⋯ The Km values of CYP2C8, CYP2C19, and CYP3A4 in bedaquiline N-demethylation were 13.1, 21.3, and 8.5 µM, respectively. We also identified a novel metabolic pathway of bedaquiline that produced an aldehyde intermediate. In summary, this study extended our knowledge of bedaquiline metabolism, which can be applied to predict and prevent drug-drug interactions and adverse drug reactions associated with bedaquiline.
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Drug Metab. Dispos. · Dec 2013
Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir.
Plasma concentrations of orally administered methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavir-lopinavir on intravenous and oral methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. ⋯ Acute and steady-state ritonavir-lopinavir stereoselectively induced methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir-lopinavir inhibited intestinal transporters activity but had no effect on methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition.
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Drug Metab. Dispos. · Sep 2013
Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism.
Activation of metabotropic glutamate receptor subtype 5 (mGlu5) represents a novel strategy for therapeutic intervention into multiple central nervous system disorders, including schizophrenia. Recently, a number of positive allosteric modulators (PAMs) of mGlu5 were discovered to exhibit in vivo efficacy in rodent models of psychosis, including PAMs possessing varying degrees of agonist activity (ago-PAMs), as well as PAMs devoid of agonist activity. However, previous studies revealed that ago-PAMs can induce seizure activity and behavioral convulsions, whereas pure mGlu5 PAMs do not induce these adverse effects. ⋯ Electrophysiological studies in rat hippocampal slices confirmed agonist activity of both M1 and VU0403602 and revealed that M1 can induce epileptiform activity in a manner consistent with its proconvulsant behavioral effects. Furthermore, unbound brain exposure of M1 was similar to that of the parent compound, VU0403602. These findings indicate that biotransformation of mGlu5 PAMs to active metabolite-ligands may contribute to the epileptogenesis observed after in vivo administration of this class of allosteric receptor modulators.
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Drug Metab. Dispos. · Apr 2013
Application of a physiologically based pharmacokinetic model to assess propofol hepatic and renal glucuronidation in isolation: utility of in vitro and in vivo data.
A physiologically based pharmacokinetic (PBPK) modeling approach was used to assess the prediction accuracy of propofol hepatic and extrahepatic metabolic clearance and to address previously reported underprediction of in vivo clearance based on static in vitro-in vivo extrapolation methods. The predictive capacity of propofol intrinsic clearance data (CLint) obtained in human hepatocytes and liver and kidney microsomes was assessed using the PBPK model developed in MATLAB software. Microsomal data obtained by both substrate depletion and metabolite formation methods and in the presence of 2% bovine serum albumin were considered in the analysis. ⋯ Optimization process highlighted that renal glucuronidation clearance was underpredicted to a greater extent than liver clearance, requiring empirical scaling factors of 17 and 9, respectively. The use of optimized clearance parameters predicted hepatic and renal extraction ratios within 20% of the observed values, reported in an additional independent clinical study. This study highlights the complexity involved in assessing the contribution of extrahepatic clearance mechanisms and illustrates the application of PBPK modeling, in conjunction with clinical data, to assess prediction of clearance from in vitro data for each tissue individually.