Bioavailability of tobramycin after oral delivery in FVB mice using CRL-1605 copolymer, an inhibitor of P-glycoprotein

doi:10.1016/S0024-3205(00)00786-4

Life Sciences

Volume 67, Issue 16, 8 September 2000, Pages 2011-2016

https://doi.org/10.1016/S0024-3205(00)00786-4 Get rights and content

Abstract

Tobramycin is an aminoglycoside used in the treatment of infection against gram-negative bacteria. Tobramycin cannot be delivered orally probably due to efflux of drug by a P-glycoprotein pump in the brush border of the small intestine. In this report we demonstrate oral delivery of tobramycin in FVB mice using CRL-1605 copolymer as a vehicle. This copolymer is known to inhibit P-glycoprotein. Two different doses of tobramycin (25 mg/kg and 200 mg/kg) were used. The concentration of CRL-1605 copolymer was 132 mg/kg. The liquid formulation was fed to mice by gavage and serum tobramycin concentrations were measured after one and two hours using the fluorescence polarization immunoassay. We observed significant increases in serum tobramycin concentrations when the drug was delivered orally with the copolymer compared to when the drug was delivered alone. We also performed a bioassay using Bacillus subtilis to confirm antibacterial effect of tobramycin in mice sera. This was to ensure that tobramycin did not undergo structural change during oral absorption when delivered in the copolymer vehicle. We observed minimal inhibition in growth of Bacillus subtilis in sera obtained from mice fed with tobramycin alone. In contrast, we observed almost complete inhibition of growth (most specimens) in sera obtained from mice fed with tobramycin in the presence of CRL-1605 copolymer. We conclude that tobramycin delivered orally in mice using copolymer 1605 is also bioactive.

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Moreover, in vivo studies showed an increase in relative bioavailability of paclitaxel for 6.3-fold in rats. Another group used CRL-105 copolymer of polyoxypropylene and polyoxyethylene blocks to increase the absorption of P-gp substrates amikacin and tobramycin in vivo in rats (Jagannath et al., 1999; Banerjee et al., 2000). In the past decade a new generation of polymers—thiolated polymers—has emerged as a promising new type of polymeric excipients for use in oral pharmaceutical formulations.
The aim of the present study was to investigate the influence of molecular mass and thiol group content of poly(acrylic acid)–cysteine conjugates on the permeation of sulforhodamine 101 and penicillin G. acting as substrates for multidrug resistance-associated protein 2 efflux pump. Poly(acrylic acids) of 2 kDa, 100 kDa, 250 kDa, 450 kDa and 3000 kDa were conjugated with cysteine. The thiol group content of all these polymers was in the range from 343.3 ± 48.4 μmol/g to 450.3 ± 76.1 μmol/g. Transport studies were performed on rat small intestine mounted in Ussing-type chambers. Since 250 kDa poly(acrylic acid) showed the highest permeation enhancing effect, additionally thiolated 250 kDa polyacrylates displaying 157.2 μmol/g, 223.0 ± 18.1 and 355.9 μmol/g thiol groups were synthesized in order to investigate the influence of thiol group content on the permeation enhancement. The permeation of sulforhodamine was 3.93- and 3.85-fold improved using 250 kDa poly(acrylic acid)–cysteine conjugate exhibiting 355.9 ± 39.5 μmol/g and 223.0 ± 18.1 μmol/g thiol groups. Using the same conjugates the permeation of penicillin G was 1.70- and 1.59-fold improved, respectively. The study demonstrates that thiolated poly(acrylic acid) inhibits Mrp2 mediated transport and that the extent of inhibition depends on the molecular mass and degree of thiolation of the polymer.
Hydroxypropyl-Sulfobutyl-β-Cyclodextrin improves the oral bioavailability of edaravone by modulating drug efflux pump of enterocytes
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However, these Pgp inhibitors were not enough to increase intracellular concentrations of anticancer drugs in clinical trials. On the contrary, Pgp inhibitors were also employed to improve the bioavailability of Pgp substrates.45-47 Nevertheless, some shortages have been considered accompanying with these effects, including the adverse effect owing to their pharmacological activities.
The objective of the study was to evaluate the effect of hydroxypropyl-sulfobutyl-β-cyclodextrin (HP-SBE-βCD) on the bioavailability and intestinal absorption of edaravone, and identify its mechanism of action. We devised HP-SBE-βCD as a carrier and modulator of P-glycoprotein (Pgp) efflux pump, and edaravone as a model drug, and prepared edaravone/HP-SBE-βCD inclusion complex. HP-SBE-βCD improved the water solubility and enhanced the bioavailability of edaravone by 10.3-fold in rats. Then, in situ single-pass intestinal perfusion showed that HP-SBE-βCD had an effect of improving the permeability and inhibiting the efflux of edaravone. Furthermore, the effects of HP-SBE-βCD on Pgp were achieved through interfering with the lipid raft and depleting the cholesterol of enterocytes membrane. From the results, we presented the novel mechanisms. First, edaravone/HP-SBE-βCD had a lower release from the inclusion compound to protect edaravone from the low pH of the stomach. Then, HP-SBE-βCD modulated the membrane microenvironment of intestinal absorption epithelial cells. At last, the result was that HP-SBE-βCD enhanced the absorption of edaravone by interfering with Pgp. In conclusion, HP-SBE-βCD improves the bioavailability of drug not only because of its enhancing water solubility of the drug, but also because it modulates the Pgp-mediated efflux from enterocytes.
Intranasal delivery of streptomycin sulfate (STRS) loaded solid lipid nanoparticles to brain and blood
2014, International Journal of Pharmaceutics
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Nevertheless, several factors like dose related toxicity, development of resistance and poor patient compliance due to the invasive therapy (streptomycin is given intramuscularly) limit its widespread use. Need for parenteral therapy is attributed to loss of its bioactivity in the acidic pH of the stomach due to ionization, poor permeability across intestinal epithelium due to its highly hydrophilic nature (log p = −6.7), a high molecular weight (1457.4 Da) and its proneness to P-gp efflux (Banerjee et al., 2000). It is indicated that STRS cannot reach across the (<10% of the administered dose) normal human brain due to its inability to cross intact blood brain barrier (BBB), while >25% of the administered STRS may reach brain in patients with tubercular meningitis due to the disruption of the BBB.
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Polymers influencing transportability profile of drug
2013, Saudi Pharmaceutical Journal
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Furthermore, it has been demonstrated that the efflux pump inhibitory effect of pluronics gets reduced when its concentration reaches toward critical micelle concentration (CMC). Banerjee et al. (2000) and Jagannath et al. (1999), in separate studies have demonstrated the PGP efflux pump inhibitory activity of CRL-1605 copolymer to improve tobramycin and amikacin oral uptake. Kabanov et al. (2003) have discussed different mechanisms behind the efflux pump inhibitory activity of pluronics and its role in the delivery of efflux pump substrates across BBB.
Drug release from various polymers is generally governed by the type of polymer/s incorporated in the formulation and mechanism of drug release from polymer/s. A single polymer may show one or more mechanisms of drug release out of which one mechanism is majorly followed for drug release. Some of the common mechanisms of drug release from polymers were, diffusion, swelling, matrix release, leaching of drug, etc. Mechanism or rate of drug release from a polymer or a combination of polymers can be predicted by using different computational methods or models. These models were capable of predicting drug release from its dosage form in advance without actual formulation and testing of drug release from dosage form. Quantitative structure–property relationship (QSPR) is an important tool used in the prediction of various physicochemical properties of actives as well as inactives. Since last several decades QSPR has been applied in new drug development for reducing the total number of drugs to be synthesized, as it involves a selection of the most desirable compound of interest. This technique was also applied in predicting in vivo performance of drug/s for various parameters. QSPR serves as a predictive tool to correlate structural descriptors of molecules with biological as well as physicochemical properties. Several researchers have contributed at different extents in this area to modify various properties of pharmaceuticals. The present review is focused on a study of different polymers that influence the transportability profiles of drugs along with the application of QSPR either to study different properties of polymers that regulate drug release or in predicting drug transportability from different polymer systems used in formulations.
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2012, European Journal of Pharmaceutical Sciences
Citation Excerpt :
It was shown that pluronic inhibited the P-gp efflux system in Caco-2 monolayers, resulting in a significant enhancement of absorption and permeability of rhodamine 123 (Batrakova et al., 1998, 1999). Furthermore, increased oral uptake of tobramicin and amikacin which could be P-gp substrates was observed in the presence of poloxamer CRL-1605 (Banerjee et al., 2000; Jagannath et al., 1999). Another study has shown that pluronic F68 can improve the pharmacokinetics of orally administered drugs that are P-gp and/or CYP3A4 substrates in vivo such as rifampicin, celiprolol and midazolam (Ma et al., 2011; Huang et al., 2008).
In order to enhance paclitaxel oral bioavailability, mixed polymeric micelles that comprised of pluronic copolymers and low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate were developed. PTX-loaded mixed polymeric micelles (MPMs) were prepared by dialysis method with high drug loading 26.92 ± 2.08% and 25.82 ± 1.9% for F127/LHR and P188/LHR MPMs respectively, and were found to be spherical in shape with an average size of around 140 nm and a narrow size distribution. In vitro release study showed that pluronic/LHR MPMs exhibited delayed release characteristics compared to Taxol and faster drug release profile compared to LHR plain polymeric micelles (PPMs). The cytotoxic activity of PTX-loaded pluronic/LHR MPMs was slightly higher than LHR PPMs in MCF-7 cells (p < 0.01). In situ effective permeability of PTX through rat small intestine was 5- to 6-fold higher with mixed micelles than that of Taxol. Moreover, pluronic/LHR MPMs achieved significantly higher AUC and C_max level than both of LHR PPMs and Taxol. This enhancement might be due to the inhibition of both P-glycoprotein efflux system and cytochrome P450 metabolism by pluronic copolymers. The current results encourage further development of paclitaxel mixed polymeric micelles as an oral drug delivery system.
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The role of transporters in drug absorption, distribution and elimination processes as well as in drug–drug interactions is increasingly being recognised. Although the lungs express high levels of both efflux and uptake drug transporters, little is known of the implications for the biopharmaceutics of inhaled drugs. The current knowledge of the expression, localisation and functionality of drug transporters in the pulmonary tissue and the few studies that have looked at their impact on pulmonary drug absorption is extensively reviewed. The emphasis is on transporters most likely to affect the disposition of inhaled drugs: (1) the ATP-binding cassette (ABC) superfamily which includes the efflux pumps P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs), breast cancer resistance protein (BCRP) and (2) the solute-linked carrier (SLC and SLCO) superfamily to which belong the organic cation transporter (OCT) family, the peptide transporter (PEPT) family, the organic anion transporter (OAT) family and the organic anion transporting polypeptide (OATP) family. Whenever available, expression and localisation in the intact human tissue are compared with those in animal lungs and respiratory epithelial cell models in vitro. The influence of lung diseases or exogenous agents on transporter expression is also mentioned. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2240–2255, 2010

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Original articleBioavailability of tobramycin after oral delivery in FVB mice using CRL-1605 copolymer, an inhibitor of P-glycoprotein

Abstract

Original article
Bioavailability of tobramycin after oral delivery in FVB mice using CRL-1605 copolymer, an inhibitor of P-glycoprotein