title: Effect of para-sulfonato-calix[n]arenes on the solubility, chemical stability, and bioavailability of a water insoluble drug nifedipine.
abstract: This study reports the use of para-sulphonato calix[8]arene to produce stable complexes with improved bioavailability for nifedipine, a calcium-channel blocker that is practically insoluble in water. Thermal analysis and electrospray ionisation mass spectroscopy confirmed that nifedipine formed complexes with the calixarenes in a size dependent way. The most stable, soluble complexes was formed with para-sulphonato calix[8]arene. Complexation was weakest with the calix[4]arene while complexation with the calix[6]arene was intermediate. However, the calix[4 and 6]arenes changed the chemical stability of the drug in solution because significant amounts of the nitroso-pyridine derivative was produced, proposing an interaction between the nifedipine bearing a H substituent at the N-1 position and the calixarenes. This oxidative degradation of the drug was greatest when combined with the calix[6]arene. Simultaneous oral ingestion of the calix[6 or 8]arenes significantly increased the bioavailability of the drug after oral administration in male Sprague-Dawley rats while not influencing CYP3A activities in the liver. The pharmacokinetic parameters of the nifedipine: para-sulfonato calix[8]arene complexes showed it was bioequivalent to a nifedipine PEG-solution. The absolute bioavailability for both formulations was ca. 60 %.
authors.affiliation: School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705-2222, USA.
authors.forename: Wenzhan
authors.initials: W
authors.lastname: Yang
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Otto
authors.forename: Wilna
authors.initials: W
authors.lastname: Liebenberg
authors.forename: Melgardt M
authors.initials: MM
authors.lastname: de Villiers
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D047250:Calixarenes / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004337:Drug Carriers; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D009543:Nifedipine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D013678:Technology, Pharmaceutical / Q000379:methods; D013810:Therapeutic Equivalency; D013818:Thermogravimetry
chemical_list: D002121:Calcium Channel Blockers; D004337:Drug Carriers; D047250:Calixarenes; D065347:Hypromellose Derivatives; D011092:Polyethylene Glycols; D008747:Methylcellulose; D051544:Cytochrome P-450 CYP3A; D009543:Nifedipine