Kwiecień Anna, Ruda-Kucerova Jana, Kamiński Kamil, Babinska Zuzana, Popiołek Iwona, Szczubiałka Krzysztof, Nowakowska Maria, Walczak Maria
Department of Inorganic and Analytical Chemistry, Jagiellonian University Medical College, Faculty of Pharmacy, Medyczna 9, 30-688 Kraków, Poland.
Department of Pharmacology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno 625 00, Czech Republic.
Pharmaceutics. 2020 Feb 16;12(2):162. doi: 10.3390/pharmaceutics12020162.
The pharmacokinetic profile and tissue uptake of daidzein (DAI) was determined in rat serum and tissues (lungs, eyes, brain, heart, spleen, fat, liver, kidney, and testes) after intravenous and intraperitoneal administration of DAI in suspension or complexed with ethylenediamine-modified γ-cyclodextrin (GCD-EDA/DAI). The absolute and relative bioavailability of DAI suspended (20 mg/kg i.v. vs. 50 mg/kg i.p.) and complexed (0.54 mg/kg i.v. vs. 1.35 mg/kg i.p.) was determined. After i.p. administration, absorption of DAI complexed with GCD-EDA was more rapid (t = 15 min) than that of DAI in suspension (t = 45 min) with a ca. 3.6 times higher maximum concentration (C = 615 vs. 173 ng/mL). The i.v. half-life of DAI was longer in GCD-EDA/DAI complex compared with DAI in suspension (t = 380 min vs. 230 min). The volume of distribution of DAI given i.v. in GCD-EDA/DAI complex was ca. 6 times larger than DAI in suspension (38.6 L/kg vs. 6.2 L/kg). Our data support the concept that the pharmacokinetics of DAI suspended in high doses are nonlinear. Increasing the intravenous dose 34 times resulted in a 5-fold increase in AUC. In turn, increasing the intraperitoneal dose 37 times resulted in a ca. 2-fold increase in AUC. The results of this study suggested that GCD-EDA complex may improve DAI bioavailability after i.p. administration. The absolute bioavailability of DAI in GCD-EDA inclusion complex was ca. 3 times greater (F = 82.4% vs. 28.2%), and the relative bioavailability was ca. 21 times higher than that of DAI in suspension, indicating the need to study DAI bioavailability after administration by routes other than intraperitoneal, e.g., orally, subcutaneously, or intramuscularly. The concentration of DAI released from GCD-EDA/DAI inclusion complex to all the rat tissues studied was higher than after administration of DAI in suspension. The concentration of DAI in brain and lungs was found to be almost 90 and 45 times higher, respectively, when administered in complex compared to the suspended DAI. Given the nonlinear relationship between DAI bioavailability and the dose released from the GCD-EDA complex, complexation of DAI may thus offer an effective approach to improve DAI delivery for treatment purposes, for example in mucopolysaccharidosis (MPS), allowing the reduction of ingested DAI doses.
在大鼠静脉注射和腹腔注射悬浮态或与乙二胺修饰的γ-环糊精（GCD-EDA/DAI）复合的大豆苷元（DAI）后，测定了大鼠血清和组织（肺、眼、脑、心脏、脾脏、脂肪、肝脏、肾脏和睾丸）中DAI的药代动力学特征和组织摄取情况。测定了悬浮态（静脉注射20 mg/kg与腹腔注射50 mg/kg）和复合态（静脉注射0.54 mg/kg与腹腔注射1.35 mg/kg）DAI的绝对生物利用度和相对生物利用度。腹腔注射后，与GCD-EDA复合的DAI吸收更快（t = 15分钟），比悬浮态DAI（t = 45分钟）快，最大浓度约高3.6倍（C = 615 ng/mL对173 ng/mL）。与悬浮态DAI相比，GCD-EDA/DAI复合物中DAI的静脉注射半衰期更长（t = 380分钟对230分钟）。静脉注射GCD-EDA/DAI复合物中DAI的分布容积比悬浮态DAI大约6倍（38.6 L/kg对6.2 L/kg）。我们的数据支持高剂量悬浮态DAI的药代动力学是非线性的这一概念。静脉注射剂量增加34倍导致AUC增加5倍。相应地，腹腔注射剂量增加37倍导致AUC增加约2倍。本研究结果表明，GCD-EDA复合物可能会提高腹腔注射后DAI的生物利用度。GCD-EDA包合物中DAI的绝对生物利用度约高3倍（F = 82.4%对28.2%），相对生物利用度比悬浮态DAI高约21倍，这表明需要研究除腹腔注射外其他给药途径（如口服、皮下或肌肉注射）后DAI的生物利用度。从GCD-EDA/DAI包合物释放到所有研究的大鼠组织中的DAI浓度均高于悬浮态DAI给药后。与悬浮态DAI相比，复合态给药时，脑和肺中DAI的浓度分别高出近90倍和45倍。鉴于DAI生物利用度与GCD-EDA复合物释放剂量之间的非线性关系，因此DAI的复合可能为改善DAI用于治疗目的（例如在黏多糖贮积症（MPS）中）的递送提供一种有效方法，从而可以减少摄入的DAI剂量。
