Indirect relationship between lipophilicity and maximum residue limit of drugs determined for fatty tissue

Marczak, Monika; Okoniewska, Krystyna Marta; Okoniewski, Jakub; Grabowski, Tomasz; Jaroszewski, Jerzy Jan

doi:10.1515/bvip-2015-0057

Cited by 6 publications

(4 citation statements)

References 19 publications

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“…RAF is a poorly watersoluble drug with a LogD of 6.76 in a pH 7.4 buffer. 14 Its solubility is less than 0.1 μg/mL in purified water, and this increases to 10.7 μg/mL in a 0.1 N sodium hydroxide (NaOH) solution. The low solubility of RAF in aqueous media is mainly attributed to its high LogD.…”

Section: Resultsmentioning

confidence: 99%

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Self-Association of Rafoxanide in Aqueous Media and Its Application in Preparing Amorphous Solid Dispersions

et al. 2017

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Our primary objective is to characterize the self-association of rafoxanide in alkaline media. The second objective is to illustrate the feasibility of using rafoxanide micellar solution as the feed solution to prepare amorphous solid dispersion via spray drying. Rafoxanide is a poorly water-soluble drug. It is a weak acid, and its poor aqueous solubility is due to its hydrophobicity. The surface-active property of rafoxanide has not been previously reported. It was discovered that the addition of a small percentage of organic solvents is required to elevate the solubility of rafoxanide above the critical micelle concentration to allow for the formation of micelles. Our fluorescence decay study confirms the self-association of rafoxanide in a cosolvent consisting of 70%, v/v, NaOH solution and 30%, v/v, acetone. The position of each functional group in the micellar structures using the H NMR technique was identified. The critical micelle concentration of rafoxanide in the cosolvent is determined to be 302 μg/mL using a surface tension method. The solubility of rafoxanide in 0.1 N NaOH solution is less than 11 μg/mL. Interestingly, the apparent solubility increased to 38,400 μg/mL in the presence of 30% acetone as the result of micelle formation. This unique solubility characteristic makes it feasible to prepare rafoxanide amorphous solid dispersions by spray drying a predominantly aqueous (70% 0.1 N NaOH solution and 30% acetone) based feed solution. Povidone and copovidone were both used as polymeric carriers. Based on solid-state characterization, including differential scanning calorimetry, X-ray powder diffraction, and hot-stage polarized light microscopy, our results indicate that rafoxanide solid dispersions prepared using this novel process are amorphous. Approximately 750-fold increase in the concentration of rafoxanide in aqueous media at pH 6.8 was achieved with the amorphous solid dispersions.

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Section: Resultsmentioning

confidence: 99%

“…RAF is a weak acid with a p K a of 4.6. RAF is a poorly water-soluble drug with a LogD of 6.76 in a pH 7.4 buffer . Its solubility is less than 0.1 μg/mL in purified water, and this increases to 10.7 μg/mL in a 0.1 N sodium hydroxide (NaOH) solution.…”

Section: Resultsmentioning

confidence: 99%

Self-Association of Rafoxanide in Aqueous Media and Its Application in Preparing Amorphous Solid Dispersions

et al. 2017

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“…The degree of tylosin binding to milk protein was reported to be 15% in another study (Ziv and Sulman, 1973). Although lipophilic drugs bind to plasma and tissue proteins at a high degree (Marczak et al, 2015), the binding ratios of drugs to milk and plasma proteins may be different (Atkinson and Begg, 1990). Also, the binding affinities of drugs to Figure 1.…”

Section: Discussionmentioning

confidence: 95%

Distribution of hydrophilic and lipophilic antibacterial drugs in skim milk, cream, and casein

Özdemir

Traş

Üney

2018

Journal of Dairy Science

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This study determined the distribution of drugs to different milk fractions according to their physicochemical properties. Hydrophilic drugs tend to concentrate in skim milk, whereas lipophilic drugs tend to concentrate in cream. The concentration of a drug in casein is related to its degree of binding to milk proteins. Thus, we aimed to determine whether withdrawal time in whole milk differs from that in cream, casein, and skim milk. Amoxicillin and tylosin were selected as prototype hydrophilic and lipophilic drugs, respectively. The study was conducted in vitro and in vivo to determine whether in vitro conditions reflect the distribution of drugs in the different milk fractions in vivo. The in vivo study was conducted using a crossover design on 6 healthy Holstein dairy cattle. First, amoxicillin (i.m., single dose, 14 mg/kg) was administered to cows. Following a 1-wk washout period, tylosin (i.m., single dose, 15 mg/kg) was administered. Concentrations of amoxicillin and tylosin in milk and milk fractions were measured using HPLC-UV. In the in vitro study, 0.04 to 400 μg/g of amoxicillin and 0.05 to 50 μg/g of tylosin were spiked to drug-free milk and the concentrations in milk and milk fractions were measured. In addition, the percentage of total protein in milk and milk fractions was determined. Amoxicillin accumulated more in skim milk than in cream and casein, both in vitro (92%) and in vivo (73%, skim milk-to-whole milk ratio). The distribution of tylosin in whole and skim milk was similar to that of amoxicillin in the in vitro study, in contrast to the accumulation of tylosin in cream seen in vivo. However, the accumulation ratio of tylosin in cream was lower than expected. By either method, tylosin was less concentrated in casein than in skim milk and cream. The percentage of total protein was similar in skim milk and whole milk and higher than in cream. Thus, amoxicillin accumulates less in cream and casein, suggesting that these fractions would pose a lower risk to the consumer. Tylosin was still present at the maximum residue limit (50 μg/kg) 24 h after injection in the casein fraction and 48 h after injection in the cream fraction.

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“…One potential method to increase the CSF concentration of ponazuril is suggested by the observation that ponazuril is a highly lipophilic compound 4 . If coadministration of ponazuril with oil enhances absorption of ponazuril this would be an economical means to enhance absorption and thereby increase serum and CSF concentrations, possibly improving effectiveness of treatment.…”

Section: Introductionmentioning

confidence: 99%

Effects of coadministration of corn oil and ponazuril on serum and cerebrospinal fluid concentrations of ponazuril in horses

Furr

Kennedy²

2020

Veterinary Internal Medicne

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Background: Ponazuril is used for the treatment of equine protozoal myeloencephalitis (EPM). Coadministration of ponazuril with oil could result in higher serum and cerebrospinal fluid (CSF) concentrations of ponazuril.Hypothesis: Coadministration of corn oil will result in higher serum and CSF concentrations of ponazuril than when ponazuril is administered alone.Animals: Ten resident university-owned adult horses of either sex and >2 years of age.Methods: Cohort study. Ponazuril oral paste (5 mg/kg BW; ponazuril treatment group (PON); n = 5), or ponazuril oral paste (5 mg/kg BW; ponazuril and oil treatment group (PONOIL; n = 5) coadministered with 2 oz of corn oil q24h for 21 days. Horses were treated once daily, for 21 days. Blood was collected on days 0, 7, 14, and 21 before dosing. In addition, CSF was collected on days 1, 7, 14, and 21. The concentration of ponazuril was determined in serum and CSF and results compared using repeated measures ANOVA.Results: Coadministration of ponazuril with 2 oz of corn oil resulted in higher concentrations of ponazuril in serum (at steady state) than that found in horses given ponazuril alone (6.2 ± 0.9 mg/L versus 4.5 ± 1.0 mg/L; P = .004) (mean ± 1 SD). Cerebrospinal fluid concentrations of ponazuril were also greater in horses that received ponazuril and oil (0.213 mg/L ± 0.04 versus 0.162 ± 0.04 mg/L) (P = .03).Conclusions and Clinical Importance: Results suggest that coadministration of corn oil with ponazuril might enhance the effectiveness of treatment with ponazuril.

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Indirect relationship between lipophilicity and maximum residue limit of drugs determined for fatty tissue

Cited by 6 publications

References 19 publications

Self-Association of Rafoxanide in Aqueous Media and Its Application in Preparing Amorphous Solid Dispersions

Self-Association of Rafoxanide in Aqueous Media and Its Application in Preparing Amorphous Solid Dispersions

Distribution of hydrophilic and lipophilic antibacterial drugs in skim milk, cream, and casein

Effects of coadministration of corn oil and ponazuril on serum and cerebrospinal fluid concentrations of ponazuril in horses

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