Thorsteinn Loftsson1, Maria D Moya-Ortega1, Carmen Alvarez-Lorenzo2, Angel Concheiro2. 1. Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland. 2. Departamento de Farmacia y Tecnología Farmacéutica, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain.
Abstract
OBJECTIVES: The objective of the present study was to shed some light on pharmacokinetics of cyclodextrins (CDs) and drugs after oral and parenteral administration of inclusion complexes. KEY FINDINGS: The complex binding constant in water can predict pharmacokinetics after parenteral administration, but it has to be considered in the context of the physiological environment, where plasma proteins compete with CDs for drug binding. Neither drug/CD nor drug/protein complexes can extravasate, but differently from proteins, CDs are readily cleared through glomerular filtration. In such intricate interrelationships, for complexes with low-to-mid binding constant, binding of drug to plasma proteins will mainly dictate the pharmacokinetics. Oppositely, for drugs showing large CD complex binding constant and low protein binding, significant decrease in distribution volume and enhanced excretion of unmetabolized drug are observed; thus, relevant changes in bioavailability can be predicted. In the case of oral administration, volume for dilution/dissolution of the complexes is relatively low and hence excess CD can hamper drug absorption from the gastrointestinal (GI) tract. SUMMARY: CDs are well-established multipurpose excipients for overcoming organoleptic and biopharmaceutical deficiencies of a variety of drugs. Balances between free and complexed drug in the GI tract and between drug-CD binding and drug-protein binding in plasma seem to play a relevant role in drug pharmacokinetics.
OBJECTIVES: The objective of the present study was to shed some light on pharmacokinetics of cyclodextrins (CDs) and drugs after oral and parenteral administration of inclusion complexes. KEY FINDINGS: The complex binding constant in water can predict pharmacokinetics after parenteral administration, but it has to be considered in the context of the physiological environment, where plasma proteins compete with CDs for drug binding. Neither drug/CD nor drug/protein complexes can extravasate, but differently from proteins, CDs are readily cleared through glomerular filtration. In such intricate interrelationships, for complexes with low-to-mid binding constant, binding of drug to plasma proteins will mainly dictate the pharmacokinetics. Oppositely, for drugs showing large CD complex binding constant and low protein binding, significant decrease in distribution volume and enhanced excretion of unmetabolized drug are observed; thus, relevant changes in bioavailability can be predicted. In the case of oral administration, volume for dilution/dissolution of the complexes is relatively low and hence excess CD can hamper drug absorption from the gastrointestinal (GI) tract. SUMMARY:CDs are well-established multipurpose excipients for overcoming organoleptic and biopharmaceutical deficiencies of a variety of drugs. Balances between free and complexed drug in the GI tract and between drug-CD binding and drug-protein binding in plasma seem to play a relevant role in drug pharmacokinetics.
Authors: Anandakrishnan Karthic; Arpita Roy; Jaya Lakkakula; Saad Alghamdi; Afnan Shakoori; Ahmad O Babalghith; Talha Bin Emran; Rohit Sharma; Clara Mariana Gonçalves Lima; Bonglee Kim; Moon Nyeo Park; Sher Zaman Safi; Ray Silva de Almeida; Henrique Douglas Melo Coutinho Journal: Front Cell Dev Biol Date: 2022-09-08