Mixed Micelles Loaded with Bile Salt: An Approach to Enhance Intestinal Transport of the BCS Class III Drug Cefotaxime in Rats.
OBJECTIVE
Cefotaxime is a class III drug according to the Biopharmaceutical Classification System due to low intestinal permeability based on poor oral bioavailability. Bile salt compounds have been shown to be effective additive for drug permeation through several biological membranes. The main purpose of this study was to investigate the ability of a mixed micelles made of phosphatidylcholine, sodium deoxycholate, and loaded with a cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex to enhance the oral bioavailability of cefotaxime in rats.


METHODS
Thin-film hydration method was used to prepare cefotaxime-loaded mixed micelles using different bile salt concentrations (0.87-25 mM of sodium deoxycholate). Overall, micelle sizes ranging from 86.9 to 155.6 nm were produced with negative zeta potential values from -15.9 to -19.5 mV and drug loading from 10.5 to 18.9 %. The oral bioavailability of cefotaxime in mixed micellar formulation was assessed and the pharmacokinetic parameters were compared with cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex and cefotaxime aqueous solution. 24 Male Wistar rats were randomly allocated into four groups (n = 6, per group) to receive the following: (1) a single intravenous dose of cefotaxime (25 mg/kg) in sterilized normal saline solution for injection; (2) a single oral dose of mixed micelles (100 mg/kg of cefotaxime) in phosphate buffered saline administered by oral gavage; (3) a single oral dose of cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex (100 mg/kg of cefotaxime) in phosphate buffered saline administered by oral gavage; (4) a single oral dose of free cefotaxime (100 mg/kg) in aqueous solution administered by oral gavage. Blood samples were collected for up to 24 h and cefotaxime analyzed using a validated HPLC assay.


RESULTS
Pharmacokinetic data showed that the oral bioavailability of cefotaxime in mixed micelles was found to be 4.91 % higher compared to the cefotaxime in aqueous solution (1.30 %). Maximum concentration (Cmax) of cefotaxime in mixed micellar formulation was higher (1.08 ± 0.1 µg/ml) compared to the cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex (0.69 ± 0.1 µg/ml) and cefotaxime in aqueous solution (0.52 ± 0.1 µg/ml). Similarly, the mean values for area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) of cefotaxime in the mixed micellar formulation was higher (3.89 ± 0.9 μg·h/mL) compared to the cefotaxime-3α,7α-dihydroxy-12-keto-5β-cholanate complex (1.52 ± 0.2 μg·h/mL) and cefotaxime in aqueous solution (1.03 ± 0.4 μg·h/mL), respectively.


CONCLUSIONS
The mixed micellar formulation was able to increase the oral bioavailability of the BCS Class III drug cefotaxime up to fourfold by enhancing drug permeation through the mucosal membrane of the small intestine.
College of Pharmacy, Al Ain University of Science and Technology, Al Ain, PO Box 64141, Al Ain, Abu Dhabi, UAE. Mosab.arafat@aau.ac.ae.
Mosab
http://orcid.org/0000-0001-9297-6745
M
Arafat
Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, UK.
Cathrin
C
Kirchhoefer
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Novi Sad, 21000, Novi Sad, Serbia.
Momir
M
Mikov
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000145:classification / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001647:Bile Acids and Salts / Q000737:chemistry*; D001682:Biological Availability; D001692:Biological Transport; D002439:Cefotaxime / Q000008:administration & dosage / Q000145:classification / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000737:chemistry*; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D008823:Micelles; D017208:Rats, Wistar
D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D004337:Drug Carriers; D008823:Micelles; D002439:Cefotaxime
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