The distribution and elimination of methotrexate in mouse blood and brain after concurrent administration of polysorbate 80

Abstract

This paper describes further exploration of the effect of polysorbate 80 on the absorption, distribution, and elimination of methotrexate (MTX). This study has confirmed the earlier finding that polysorbate 80 could increase the absorption of MTX from the mouse gastrointestinal tract and enhance the drugs uptake into the brain. The experiments reported here suggest that polysorbate 80 has a direct effect on the blood-brain barrier leading to the increased uptake of MTX, which is evident following IV administration. Measurements of MTX excreted in the urine and faeces confirmed the role of polysorbate 80 in facilitating the excretion of MTX into the bile and urine. Polysorbate 80 administered PO did not cause any reduction of plasma volume, thus excluding the possibility that the higher MTX concentrations measured in mice after concurrent administration of polysorbate PO might result from a reduction in blood volume due to osmotic effects. At the doses given, polysorbate 80 appeared not to have a damaging effect on the gastrointestinal mucosa.

The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration

“…formulations of cyclosporine (Strickley, 2004). While intravenous administration of both ethanol and Tween-80 has been reported to enhance bloodbrain barrier penetration of drugs (Hanig et al, 1972;Azmin et al, 1985;Sakane et al, 1989), the small amounts administered orally in the present study (0.025 mL each) are unlikely to affect the CNS penetration of the macrocyclic peptide, and much higher oral doses of Tween-80 (6.4 g·kg -1 ·day -1 for 28 days) were tolerated in C57BL/6J mice without evidence of cytotoxicity (Li et al, 2011). It should be noted, however, that Tween-80 may inhibit efflux proteins such as P-glycoprotein, although the evidence is mixed (Goole et al, 2010).…”

The blood-brain barrier: Bottleneck in brain drug development

“…[27][28][29][30] There are numerous examples in the literature where the peripheral administration of a drug, which normally should not cross the BBB, is followed by pharmacological activity in the brain. Such an observation could arise because the drug is transported across the BBB via an endogenous transport system.…”

Low central nervous system penetration of N2,N4,N6,-trihydroxymethyl-N2,N4,N6,-trimethylmelamine (Trimelamol): A cytotoxic s-triazine with reduced neurotoxicity

“…Other surfactants, e.g. polysorbate 80, are known to change the volume of distribution of certain drugs and may enhance their uptake into the CNS possibly by disrupting the blood-brain barrier (Azmin et al, 1985). The reason for the increase in plasma concentration at 30 min is unclear.…”