G. Gottipati, J. Venitz; Virginia Commonwealth University, Richmond, VA

BACKGROUND: The aim was to develop and validate QSPKR models for predicting biologically relevant human in vivo PK properties and in vitro relative receptor binding affinities (RRA) based on molecular and physicochemical properties (PC) for TRP.
METHODS: In vivo systemic PK properties, i.e., CLtot, Vdss and fe following IV administration of TRP to healthy humans were compiled from the literature and corrected for fu (from in vitro plasma protein binding studies) to obtain biologically relevant PK variables, namely Vdssu, CLtotu, CLrenu and CLnonrenu. RRA (Ki) of TRP to 5-HT1B/1D were compiled from in vitro and/or ex vivo studies. Pertinent PC properties were obtained from SciFinder Scholar. Univariate relationships after log-transformation were explored (r2 ≥ 0.3, p < 0.05) by linear regression (LR), and final QSPKR model building was performed by stepwise multiple LR in JMP Pro 10.0.1. Cross-validation (CV) was done using the Leave-Out-One method in RStudio v0.96.330; CV-explained variance, q2 of ≥ 0.4 was considered acceptable.
RESULTS: The final PK database consisted of seven TRP. Molecular weight (MW) - which was highly correlated with logD7.4 - showed a negative association with fu (r2 = 0.78, n = 7), and positive associations with Vdssu (r2 = 0.58, n = 7), CLtotu (r2 = 0.65, n = 7) and CLnonrenu (r2 = 0.58, n = 7), but no trend with Kis. Final validated QSPKR-model predictions were acceptable (q2 = 0.59) for fu only.
CONCLUSION: MW was found to be the major determinant affecting the systemic disposition of TRP - suggesting that molecular size may govern their interactions with plasma/tissue proteins, drug metabolizing enzymes (e.g., monoamine oxidase) and drug transporters. None of the PC properties correlated with the Kis, consistent with the high molecular selectivity of drug-receptor interactions.