Host–Guest Interactions between Candesartan and Its Prodrug Candesartan Cilexetil in Complex with 2-Hydroxypropyl-β-cyclodextrin: On the Biological Potency for Angiotensin II Antagonism

Abstract

Renin−angiotensin aldosterone system inhibitors are for a long time extensively used for the treatment of cardiovascular and renal diseases. AT1 receptor blockers (ARBs or sartans) act as antihypertensive drugs by blocking the octapeptide hormone Angiotensin II to stimulate AT1 receptors. The antihypertensive drug candesartan (CAN) is the active metabolite of candesartan cilexetil (Atacand, CC). Complexes of candesartan and candesartan cilexetil with 2-hydroxylpropyl-β-cyclodextrin (2-HP-β-CD) were characterized using high-resolution electrospray ionization mass spectrometry and solid state 13 C cross-polarization/magic angle spinning nuclear magnetic resonance (CP/MAS NMR) spectroscopy. The 13 C CP/MAS results showed broad peaks especially in the aromatic region, thus confirming the strong interactions between cyclodextrin and drugs. This experimental evidence was in accordance with molecular dynamics simulations and quantum mechanical calculations. The synthesized and characterized complexes were evaluated biologically in vitro. It was shown that as a result of CAN's complexation, CAN exerts higher antagonistic activity than CC. Therefore, a formulation of CC with 2-HP-β-CD is not indicated, while the formulation with CAN is promising and needs further investigation. This intriguing result is justified by the binding free energy calculations, which predicted efficient CC binding to 2-HP-β-CD, and thus, the molecule's availability for release and action on the target is diminished. In contrast, CAN binding was not favored, and this may allow easy release for the drug to exert its bioactivity.

Investigation of Praziquantel/Cyclodextrin Inclusion Complexation by NMR and LC-HRMS/MS: Mechanism, Solubility, Chemical Stability, and Degradation Products

“…Mass spectrometry, an efficient technique to study noncovalent complexes, can be used to determine the stoichiometry of host/guest complexes in the gas phase, which can be correlated with the behavior in solutions. , Solutions of PZQ with selected CDs were analyzed by HRMS. Signals corresponding to 1:1 PZQ/CD complexes were observed indicating the formation of inclusion complexes (Table ).…”

Preparation and Biophysical Characterization of Quercetin Inclusion Complexes with β-Cyclodextrin Derivatives to be Formulated as Possible Nose-to-Brain Quercetin Delivery Systems

“…The relative fluorescence intensity was increased dramatically, as it exhibited a final 4.8- and 3.2-fold rise in the presence of 5 mM HP-β-CD (Figure A,Β) at pH 4.5 and 6.8, respectively. The fluorescence enhancement is usually observed when a small molecule interacts with CD due to the changes occurring in the microenvironment of the small molecule upon encapsulation. − The quantum yield of Que rises, leading to a higher fluorescence intensity as it is transferred from the aqueous solution into the hydrophobic cavity of 2-HP-β-CD. The interaction of Que with 2HP-β-CD was calculated as described above by applying the Benesi–Hildebrand equation (Figure ).…”

<p>Applying Different Techniques to Improve the Bioavailability of Candesartan Cilexetil Antihypertensive Drug</p>

“…Similar results of the CC docking pose with HP-β-CD have been reported recently. 46 To sum up, the differences observed in the binding energy, as well as the number and the type of interactions between CC-β-CD and CC-HP-β-CD complexes, approve the higher affinity of CC towards HP-β-CD rather than β-CD. This calculation associated well with the experimental stability constants values of CC with β-CD and HP-β-CD.…”