Pharmacokinetic interactions related to the chemical structures of fluoroquinolones

Abstract

Fluoroquinolone derivatives interact with methylxanthines (theophylline, caffeine) and metallic ion-containing drugs to different degrees. The rat appears to be a suitable model for predicting such interactions in man. It has been possible to determine the relationship between the chemical structure of the fluoroquinolone and the magnitude of the interaction. Fluoroquinolones with a bulky substituent at the position 8, such as sparfloxacin, lomefloxacin and fieroxacin, are less prone to interact with theophylline than those without an 8-substituent, such as enoxacin. This substituent determines the planarity of the whole fluoroquinolone molecule and the interaction tends to be more significant for planar fluoroquinolones. Furthermore, a 4'-nitrogen atom in the 7-piperazinyl group is essential for the interaction to occur. The nitrogen atom is possibly the site that binds cytochrome P-450, which catalyses theophylline metabolism. The reduction in bioavailability of fluoroquinolones by concurrent administration of aluminium hydroxide is more striking for derivatives with fewer substituents on the essential structure and on the piperazinyl group, such as norfloxacin, ciprofloxacin and enoxacin. Substitution at the 5-position diminishes the interaction, which suggests that the 5-substituent may affect the formation and/or stability of unabsorbable chelate complex which is the probable cause of the interaction. These findings are potentially useful in designing fluoroquinolones less prone to drug interactions.

Hetero-association of aromatic molecules in aqueous solution

“…Such guest molecules, which do not chemically affect the drug, are called 'interceptors' and are currently considered as a means of directed regulation of a biological effect via changing the structure and the concentration of the interceptor [42,43]. The importance of hetero-association is manifested in a long-established correlation of the hetero-association constant, K h , with an in vitro biological effect for a range of aromatic mutagens [19,44] -a rare example when a physico-chemical parameter of molecular interaction has a direct link with a biological effect (c) complexation between a drug and the guest molecule results in alteration of the bio-kinetics of absorption of the drug in the biosystem and subsequent changes to its medico-biological effect [42,45,46] (d) the hetero-association of natural aromatic polyphenol molecules with other naturally occurring aromatic substances (such as chlorogenic acid, caffeine and gallic acid) is considered to be a mechanism responsible for or to significantly influence various important biochemical processes, such as copigmentation [47,48] and tea creaming [49] (5) Pharmaceutical chemistry application (Hydrotropes). Hetero-association is considered to be the basic mechanism responsible for the widely observed enhancement of the solubility of poorly soluble aromatic drugs in the presence of other aromatic molecules, commonly referred to as hydrotropes [50, 51] (6) Medicinal chemistry application.…”

Crystal structure of di-aqua-bis-[1-cyclopropyl-7-(4-ethylpiperazin-1-yl)- 6-fluor-4-oxo-1,4-dihydrochinolin-3-carboxylic acid]zinc(II)bibenzene- 1,4-dicarboxylate octahydrate [Zn(C19H22N3FO3)2(H2O)2]·2(C8H5O4)·8(H2O), C54H74F2N6O24Zn

“…Enrofloxacin (Henro),C 19 H 22 FN 3 O 3 (systematic name: 1-cyclopropyl-7-(4-ethylpiperazin-1-yl)-6-fluor-4-oxo-1,4-dihydrochinolin-3-carboxylic acid), is am ember of the fluoroquinolone (flqu) family of antibiotics [1], widely used in veterinary clinical practice because of its wide antibiotic spectrum and its excellent bactericidal activity [1,2]. Our interest in enrofloxacin and related fluoroquinolones is focused on their potential as multidentate/bridging ligands in coordination chemistry.…”

Lack of Pharmacokinetic Interaction between Linezolid and Antacid in Healthy Volunteers

“…Multiple administrations of antacids may also alter urinary pH and increase the renal elimination of tetracyclines (17). The oral bioavailability of the fluoroquinolones amifloxacin, ciprofloxacin, norfloxacin, and ofloxacin was significantly reduced by coadministration with (aluminum-hydroxide containing) antacids (15,18,19,28). This reduced bioavailability may be caused by the formation of insoluble chelates with the 3-carbonyl and 4-oxo groups of the antibiotics and aluminum and magnesium ions.…”

“…The absorption of drugs composed of phenol rings and/or heterocycles containing atoms with free electron pairs, among which are the fluoroquinolones (15,18,19,28) and tetracyclines (6), has been shown to be decreased by polyvalent cations. The linezolid molecule contains an oxazolidinone ring system and a peptide bond (Fig.…”