Role of Transporters and Enzymes in Metabolism and Distribution of 4-Chlorokynurenine (AV-101).

4-Chlorokynurenine (4-Cl-KYN, AV-101) is a prodrug of a NMDA receptor antagonist and is in clinical development for potential CNS indications. We sought to further understand the distribution and metabolism of 4-Cl-KYN, as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays, and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood-brain barrier via LAT1. 4-Cl-KYN and its metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite has the potential to limit the excretion of a range of compounds. Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.

Youth focused life skills training and counselling services program-An inter-sectoral initiative in India: Program development and preliminary analysis of factors affecting life skills.

OBJECTIVES: This paper describes the methodology of developing and implementation of a youth focused life skills training and counselling services programme (LSTCP) and assessment of factors associated with life skills of participants pre-training. DESIGN: Development of all aspects of LSTCP (modules, methods and evaluation) was through a consultative process. Experiential learning based facilitation was decided as the approach for training participants. A quasi-experimental design with pre, post and follow-up assessment post-training was finalised. Data collection was done using specifically developed semi-structured self-administered questionnaire. RESULTS: Multivariable logistic regression with life skills as outcome and various exposure variables was performed. About 2/3rd of participants had high level of life skills (68%). Increased score of extraversion (AOR = 1.57,95% CI = 1.32-1.85), agreeableness (AOR = 1.42,95% CI = 1.16-1.73), conscientiousness (AOR = 1.9,95% CI = 1.55-2.33), physical (AOR = 1.03,95% CI = 1.01-1.04), environmental (AOR = 1.02,95% CI = 1.004-1.03) and social quality of life (AOR = 1.01,95% CI = 1.006-1.02) were associated with high life skills score. Higher score of neuroticism (AOR = 0.66,95% CI = 0.53-0.79) was associated with low life skills score. CONCLUSION: The results presented provide an opportunity to understand the evolution of factors affecting life skills during the follow-up of this study. This study throws light on development of LSTCP for apparently healthy population in a setting like India and its states.