Utilization of OATP1B Biomarker Coproporphyrin-I to Guide Drug-Drug Interaction Risk Assessment: Evaluation by the Pharmaceutical Industry.

Drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptides 1B1/1B3 (OATP1B) can be substantial, however, challenges remain for predicting interaction risk. Emerging evidence suggests that endogenous biomarkers, particularly coproporphyrin-I (CP-I), can be used to assess in vivo OATP1B activity. The present work under the International Consortium for Innovation and Quality in Pharmaceutical Development was aimed primarily at assessing CP-I as a biomarker for informing OATP1B DDI risk. Literature and unpublished CP-I data along with pertinent in vitro and clinical DDI information were collected to identify DDIs primarily involving OATP1B inhibition and assess the relationship between OATP1B substrate drug and CP-I exposure changes. Static models to predict changes in exposure of CP-I, as a selective OATP1B substrate, were also evaluated. Significant correlations were observed between CP-I area under the curve ratio (AUCR) or maximum concentration ratio (Cmax R) and AUCR of substrate drugs. In general, the CP-I Cmax R was equal to or greater than the CP-I AUCR. CP-I Cmax R < 1.25 was associated with absence of OATP1B-mediated DDIs (AUCR < 1.25) with no false negative predictions. CP-I Cmax R < 2 was associated with weak OATP1B-mediated DDIs (AUCR < 2). A correlation was identified between CP-I exposure changes and OATP1B1 static DDI predictions. Recommendations for collecting and interpreting CP-I data are discussed, including a decision tree for guiding DDI risk assessment. In conclusion, measurement of CP-I is recommended to inform OATP1B inhibition potential. The current analysis identified changes in CP-I exposure that may be used to prioritize, delay, or replace clinical DDI studies.

Reversible his-tagged enzyme immobilization on functionalized carbon nanotubes as nanoscale biocatalyst.

Common enzyme immobilization methods on nanomaterials (adsorption, covalent binding, crosslinking, encapsulation) often generate problems in enzyme leaching, 3D structure change and diffusion resistance. We show here a detailed site-specific enzyme immobilization method that overcomes the foresaid limitations. It is based on the specific interaction between His-tagged enzyme and single-walled carbon nanotubes modified with N (α) ,N (α)-bis(carboxymethyl)-L: -lysine hydrate. This method does not require enzyme purification and the resulting nanoscale biocatalyst can maintain high enzyme activity and stability. The enzyme-loading capacity is also comparable with the reported immobilization capacity on carbon nanotubes by either covalent binding or adsorption. Furthermore, the immobilization is reversible for several cycles while maintaining high enzyme activity and the nanoscale biocatalyst can be regenerated easily.