Pharmacokinetic characteristics of agents applied in the treatment of Parkinson’s disease

Nomoto, Masahiro; Nagai, Masahiro; Nakatsuka, Akiko; Nishikawa, Noriko; Yabe, Hayato; Moritoyo, Hiroyoko; Moritoyo, Takashi; Nomura, Takuo

doi:10.1007/s00415-006-3010-x

Cited by 4 publications

(1 citation statement)

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“…Indeed, the affinity of drugs for HSA is one of the most important factors affecting their free active concentration (15,28,33,39,44). Despite the relevance of peripheral DOPA-decarboxylase inhibitors and dopamine agonists administered in the management and treatment of PD, little is known about their pharmaco-kinetic and -thermodynamic properties (45). Apomorphine was investigated as a prototypical dopamine agonist in terms of binding to serum and tissue proteins by radiolabeled ligand ultrafiltration and dialysis techniques, showing that apomorphine is bound greater than 90% to serum proteins at pharmacological concentration (46).…”

Section: Discussionmentioning

confidence: 99%

Binding of anti‐Parkinson's disease drugs to human serum albumin is allosterically modulated

et al. 2010

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Binding of drugs to plasma proteins is an important determinant for their efficacy because it modulates drug availability to the intended target. Co‐administered drugs may bind to the same protein site or to different functionally linked clefts following competitive and allosteric mechanisms. Here, we report a thermodynamic and computational characterization of the binding mode of apomorphine and benserazide, two therapeutic agents co‐administered in the treatment of Parkinson's disease, to human serum albumin (HSA). Apomorphine binds to HSA with a simple equilibrium (Kd = 3.1 × 10−6 M). Conversely, benserazide binds to HSA with two independent equilibria (Kd1≤ 10−6 M and Kd2 = 5.0 × 10−5 M). Values of Kd and Kd2 increase to 1.5 × 10−5 M and 5.0 × 10−4 M, respectively, in the presence of heme. Accordingly, the Kd value for heme binding to HSA increases from 5.0 × 10−7 M to 4.8 × 10−6 M and 9.2 × 10−7 M, in the presence of saturating amounts of apomorphine and benserazide, respectively. The Kd1 value for benserazide binding to HSA is not affected by heme binding, whereas apomorphine and benserazide inhibit warfarin binding to HSA, and vice versa. Therefore, apomorphine and the second benserazide molecule bind to the warfarin site, allosterically linked to the heme site. Simulated docking of apomorphine and benserazide into the warfarin site provides favorable values of intermolecular energy (−23.0 kJ mol−1 and −15.2 kJ mol−1, respectively). Considering the apomorphine, benserazide, and HSA‐heme plasma levels and the possible co‐administration of warfarin, these results appear relevant in the management of patients affected by Parkinson's disease. © 2010 IUBMB IUBMB Life, 62(5): 371–376, 2010

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