Albendazole-praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity
Albendazole-praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity
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DOI：
10.1111/j.1365-2125.2010.03874.x
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发表时间：
2011-04-01
影响因子：
3.4
通讯作者：
Lanchote, Vera Lucia
中科院分区：
文献类型：
--
作者：
Lima, Renata Monteiro;Drago Ferreira, Maria Augusta;Lanchote, Vera Lucia
阿苯达唑和吡喹酮之间的药代动力学相互作用基于两种药物的对映体混合物的血浆浓度，数据相互矛盾，尽管抗寄生虫活性来自(-)-(R)-吡喹酮和(+)-阿苯达唑亚砜。阿苯达唑和吡喹酮的药代动力学相互作用具有对映选择性。吡喹酮对(+)-阿苯达唑亚砜血浆浓度的升高高于(-)-阿苯达唑亚砜，且阿苯达唑对(+)-(S)-吡喹酮的动力学处置没有改变，但增加了(-)-(R)-吡喹酮的血浆浓度。目的研究阿苯达唑（ABZ）和吡喹酮（PZQ）单独和联合给药对健康志愿者的动力学配置、代谢和对端选择性。方法随机交叉研究分为三期（n = 9），其中部分受试者进入第1期（400 mg ABZ），部分受试者进入第2期（1500 mg PZQ），其余受试者进入第3期（400 mg ABZ + 1500 mg PZQ）。在给药后0 ~ 48 h连续采集血液样本。采用带滞后时间的单室模型计算药代动力学参数，采用Wilcoxon检验进行分析；P < 0.05。结果PZQ使(+)- asox（阿苯达唑砜）血浆浓度增加264% (AUC 0.99比2.59 μ g ml-1 h), (-)- asox增加358% (AUC 0.14比0.50 μ g ml-1 h)，阿苯达唑砜（ASON）血浆浓度增加187%（0.17比0.32 μ g ml-1 h）。给药ABZ未改变(+)-(S)- pzq (-)-(R)-4- ohpzq或(+)-(S)-4- ohpzq的动力学配置，但使血浆(-)-(R)- pzq浓度增加了64.77% （AUC 0.52 vs. 0.86 μ g ml-1 h）。结论ABZ与PZQ在健康志愿者体内的药动学相互作用可通过观察ASON、ASOX对映体和(-)-(R)-PZQ的血浆浓度升高来证实。临床上，ABZ与PZQ合用可提高两种活性药物的浓度，从而提高治疗效果。另一方面，这种升高的幅度可能意味着副作用的风险增加，当然需要减少剂量。然而，需要进一步的研究来评估这种组合的有效性和安全性。
center dot Pharmacokinetic interactions between albendazole and praziquantel are based on plasma concentrations of the enantiomeric mixture of both drugs with contradictory data, although the antiparasitic activity arises from (-)-(R)-praziquantel and (+)-albendazole sulfoxide.WHAT THIS STUDY ADDScenter dot The pharmacokinetic interaction between albendazole and praziquantel is enantioselective. Praziquantel increased the plasma concentrations of (+)-albendazole sulfoxide more than those of (-)-albendazole sulfoxide and the administration of albendazole did not change the kinetic disposition of (+)-(S)-praziquantel, but increased the plasma concentration of (-)-(R)-praziquantel.AIMThis study investigated the kinetic disposition, metabolism and enantioselectivity of albendazole (ABZ) and praziquantel (PZQ) administered alone and in combination to healthy volunteers.METHODSA randomized crossover study was carried out in three phases (n = 9), in which some volunteers started in phase 1 (400 mg ABZ), others in phase 2 (1500 mg PZQ), and the remaining volunteers in phase 3 (400 mg ABZ + 1500 mg PZQ). Serial blood samples were collected from 0-48 h after drug administration. Pharmacokinetic parameters were calculated using a monocompartmental model with lag time and were analyzed using the Wilcoxon test; P < 0.05.RESULTSThe administration of PZQ increased the plasma concentrations of (+)-ASOX (albendazole sulphoxide) by 264% (AUC 0.99 vs. 2.59 mu g ml-1 h), (-)-ASOX by 358% (0.14 vs. 0.50 mu g ml-1 h) and albendazole sulfone (ASON) by 187% (0.17 vs. 0.32 mu g ml-1 h). The administration of ABZ did not change the kinetic disposition of (+)-(S)-PZQ (-)-(R)-4-OHPZQ or (+)-(S)-4-OHPZQ, but increased the plasma concentration of (-)-(R)-PZQ by 64.77% (AUC 0.52 vs. 0.86 mu g ml-1 h).CONCLUSIONSThe pharmacokinetic interaction between ABZ and PZQ in healthy volunteers was demonstrated by the observation of increased plasma concentrations of ASON, both ASOX enantiomers and (-)-(R)-PZQ. Clinically, the combination of ABZ and PZQ may improve the therapeutic efficacy as a consequence of higher concentration of both active drugs. On the other hand, the magnitude of this elevation may represent an increased risk of side effects, requiring, certainly, reduction of the dosage. However, further studies are necessary to evaluate the efficacy and safety of this combination.