Canine orosomucoid (alpha-1 acid glycoprotein) variants and their influence on drug plasma protein binding.
Canine orosomucoid (alpha-1 acid glycoprotein) variants and their influence on drug plasma protein binding.
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DOI：
10.1111/jvp.12899
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发表时间：
2021-01
影响因子：
1.3
通讯作者：
Mealey KL
中科院分区：
文献类型：
--
作者：
Costa AP;Court MH;Villarino NF;Burke NS;Mealey KL
Orosomucoid多态性影响人类血浆药物结合，然而，犬类变异及其对药物血浆蛋白结合的影响尚未报道。在本研究中，对100只狗的orosomucoid基因（ORM1）进行了测序，以确定最常见的变异，并在1464只狗（来自64个品种和混合品种的狗）中确定了其等位基因频率。利用ORM1基因型犬血浆（n=12）进行平衡透析，评估阿米替林、茚地那韦、维拉帕米和利多卡因的血浆蛋白结合程度。用液相色谱-质谱法测定游离和总药物血浆浓度。在犬ORM1中鉴定的五个多态性中，有两个是非同义的。最常见的等位基因为c.70G>A (p.Ala24Thr)，等位基因频率为11.2% （n=1464）。变异等位基因频率因品种而异，在设得兰牧羊犬中达到74% （n=21）。c.70AA基因型犬（n=4）和c.70GG基因型犬（n=8）血浆游离药物组分差异无统计学意义（P < 0.05; Mann-Whitney U）。虽然c.70G>A在我们的研究中没有影响血浆蛋白结合的程度，但这种新发现的ORM1变异在狗体内的潜在生物学和药理学意义有待进一步研究。
Orosomucoid polymorphisms influence plasma drug binding in humans, however, canine variants and their effect on drug plasma protein binding has not yet been reported. In this study, the orosomucoid gene (ORM1) was sequenced in 100 dogs to identify the most common variant and its allele frequency determined in 1464 dogs (from 64 breeds and mixed-breed dogs). Plasma protein binding extent of amitriptyline, indinavir, verapamil and lidocaine were evaluated by equilibrium dialysis using plasma from ORM1 genotyped dogs (n=12). Free and total drug plasma concentrations were quantified by liquid chromatography–mass spectrometry. From the five polymorphisms identified in canine ORM1, two were nonsynonymous. The most common was c.70G>A (p.Ala24Thr) with an allele frequency of 11.2% (n=1464). Variant allele frequencies varied by breed, reaching 74% in Shetland Sheepdogs (n=21). Free drug fractions did not differ significantly (P>0.05; Mann-Whitney U) between plasma collected from dogs with c.70AA (n=4) and those with c.70GG (n=8) genotypes. While c.70G>A did not affect the extent of plasma protein binding in our study, the potential biological and pharmacological implication of this newly discovered ORM1 variant in dogs should be further investigated.
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影响因子：
1.3
作者：
Costa, A.;Sellon, R. K.;Mealey, K. L.
通讯作者：
Mealey, K. L.
影响因子：
4.1
作者：
Harley, J.;Roberts, R.;Kennedy, M.
通讯作者：
Kennedy, M.
影响因子：
2.1
作者：
Matsumoto, Kazuaki;Sukimoto, Katsuaki;Otagiri, Masaki
通讯作者：
Otagiri, Masaki
影响因子：
6.7
作者：
Colombo, Sara;Buclin, Thierry;Eap, Chin B.
通讯作者：
Eap, Chin B.
DOI：
10.1097/00008571-199610000-00004
发表时间：
1996-10-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Herve, F;Duche, JC;Tillement, JP
通讯作者：
Tillement, JP