The binding of orally dosed hydrophobic active pharmaceutical ingredients to casein micelles in milk.

Casein proteins (αS1-, αS2-, ß- and κ-casein) account for 80% of the total protein content in bovine milk and form casein micelles (average diameter = 130 nm, approximately 1015 micelles/mL). The affinity of native casein micelles with the 3 hydrophobic active pharmaceutical ingredients (API), meloxicam [351.4 g/mol; log P = 3.43; acid dissociation constant (pKa) = 4.08], flunixin (296.2 g/mol; log P = 4.1; pKa = 5.82), and thiabendazole (201.2 g/mol; log P = 2.92; pKa = 4.64), was evaluated in bovine milk collected from dosed Holstein cows. Native casein micelles were separated from raw bovine milk by mild techniques such as ultracentrifugation, diafiltration, isoelectric point precipitation (pH 4.6), and size exclusion chromatography. Acetonitrile extraction of hydrophobic API was then done, followed by quantification using HPLC-UV. For the API or metabolites meloxicam, 5-hyroxy flunixin and 5-hydroxy thiabendazole, 31 ± 3.90, 31 ± 1.3, and 28 ± 0.5% of the content in milk was associated with casein micelles, respectively. Less than ∼5.0% of the recovered hydrophobic API were found in the milk fat fraction, and the remaining ∼65% were associated with the whey/serum fraction. A separate in vitro study showed that 66 ± 6.4% of meloxicam, 29 ± 0.58% of flunixin, 34 ± 0.21% of the metabolite 5-hyroxy flunixin, 50 ± 4.5% of thiabendazole, and 33 ± 3.8% of metabolite 5-hydroxy thiabendazole was found partitioned into casein micelles. Our study supports the hypothesis that casein micelles are native carriers for hydrophobic compounds in bovine milk.

Residue uptake and storage responses of Tarocco blood oranges after preharvest thiabendazole spray and postharvest heat treatment.

Tarocco blood oranges (Citrus sinensis Linn. Obsek) were subjected to a single preharvest spray with thiabendazole (TBZ) at a concentration of 1% active ingredient (ai) in water and harvested 2 weeks after fungicide application or heated at 37 degrees C for 48 h under saturated humidity after harvest. The two treatments were also combined before cold quarantine (3 weeks at 2 degrees C), subsequent storage (3 weeks at 8 degrees C), and simulated marketing period (SMP) (1 week at 20 degrees C). Fruit not treated with TBZ and unheated were used as controls. The residue levels of TBZ (active ingredient, whole fruit basis) after spray were approximately 6.3 and 5.4 mg x kg(-1) before fruit storage respectively, a level close to the tolerance limit set by the European Community. TBZ showed a high persistence during quarantine, storage, and SMP. TBZ spray significantly reduced the incidence and severity of chilling injury (CI) and decay during the postquarantine period and SMP. Heat treatment (HT) produced beneficial effects in controlling CI, especially during SMP, when applied in combination with TBZ. However, HT remarkably promoted the development of secondary fungal infections such as Phytophthora rots and adversely affected fruit flavor and taste. The occurrence of off-flavor and off-taste was found to be perceptible after heating.

The carry-through of residues of thiabendazole, tecnazene and chlorpropham from potatoes following manufacture into potato crisps and jacket potato crisps.

Potatoes, commercially treated with thiabendazole, tecnazene and chlorpropham, were processed into potato crisps and jacket potato crisps at a crisp factory using standard manufacturing conditions. A multi-residue method based on gas chromatography with mass spectrometric detection was developed and used to determine pesticide residue levels in the potatoes and potato crisps. Results showed that the residues of all three pesticides were significantly reduced to less than 2% and less than 10% of the maximum theoretical residue carry-through level for potato crisps and jacket potato crisps respectively.

The maternal-foetal distribution of thiabendazole administered in two different vehicles to pregnant mice.

We have compared the effects of two vehicles on the maternal-foetal distribution of 14C-thiabendazole ([14C]TBZ) given orally to Jcl: ICR mice on day 9 or 16 of gestation. TBZ, either suspended in olive oil (TBZ-O) or in a 0.5% aqueous solution of gum arabic (TBZ-G), was given orally on day 9 of gestation at a dose of 1 g/kg body weight (1 microCi/mouse). The mice were killed 0.5, 1, 3, 6, 12, 24 or 72 hr later. In mice treated with TBZ-O maximum levels of radioactivity in plasma and conceptuses were observed at 0.5 hr, whereas in those treated with TBZ-G maximum 14C levels were observed at 6 hr. The uptake of radioactivity from TBZ-O into the plasma and conceptuses was significantly higher than that from TBZ-G. Only trace levels of radioactivity were detected at 72 hr in both treatment groups. The placental transfer of [14C]TBZ was examined in mice treated with doses of 1 g/kg body weight (1 microCi/mouse) given as TBZ-O or TBZ-G on day 16 of gestation. The radioactivity in foetuses, placentas and maternal plasma was higher in mice treated with TBZ-O than those given TBZ-G. The placental transfer of [14C]TBZ was also examined by whole-body autoradiography in mice treated on day 16 of gestation.