Enzymatic hydrolysis of haloperidol decanoate and its inhibition by proteins

Nambu, Keiko; Miyazaki, Hisashi; Nakanishi, Yoshinobu; Oh-E, Yoshinori; Matsunaga, Yoshimasa; Hashimoto, Masahisa

doi:10.1016/0006-2952(87)90058-x

Cited by 23 publications

(14 citation statements)

References 14 publications

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“…Plasma protein binding of these esters may be the cause of the observed stabilizing effect. Stabilization of bioreversible derivatives in vitro in human plasma relative to aqueous buffer due to plasma protein binding has been found previously for a glutaric acid derivative of phenol [37], various alkyl and aromatic esters of timolol [40,41], a t-butyl ester of L-dopa [42], a basic carbamate of 4-hydroxyanisole [43], and haloperidol decanoate [44]. With the exception of t-butyl phenyl carbonate (2), reconversion to phenol proceeds more slowly for the carbonate esters 4-8 negatively charged at physiological pH than for the neutral derivatives.…”

Section: Hydrolysis In Biological Mediasupporting

confidence: 54%

Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media

Østergaard

Larsen

2007

Molecules

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Abstract:With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving the pharmacokinetics of drug substances, a series of model carbonate ester prodrugs of phenol, encompassing derivatives with fatty acid-like structures, were characterized in vitro. Stability of the derivatives was studied in aqueous solution, human serum albumin solution, human plasma, and rat liver homogenate at 37 o C. Stability of the derivatives in aqueous solution varied widely, with half-lives ranging from 31 to 1.7 × 10 4 min at pH 7.4and 37 o C. The carbonate esters were subject to catalysis by plasma esterases except for the t-butyl and acetic acid derivatives, which were stabilized in both human plasma and human serum albumin solutions relative to buffer. In most cases, however, hydrolysis was accelerated in the presence of human serum albumin indicating that the derivatives interacted with the protein, a finding which was confirmed using the p-nitrophenyl acetate kinetic assay. Different human serum albumin binding properties of the phenol model prodrugs with fatty acid-like structure and neutral carbonate esters were observed. In the context of utilizing plasma protein binding in combination with the prodrug approach for optimizing drug pharmacokinetics, the esterase-like properties of human serum albumin towards the carbonate esters potentially allowing the protein to act as a catalyst of parent compound regenerations is interesting.

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Section: Hydrolysis In Biological Mediasupporting

confidence: 54%

Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media

Østergaard

Larsen

2007

Molecules

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“…34,[50][51][52][53] However, the endogenous substrates for this family of enzymes are not well characterized. CES-2 is well known in the cancer chemotherapy field because the enzyme hydrolyzes the prodrug CPT11 to form the active metabolite SN38, which inhibits topoisomerase I.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional activation of the carboxylesterase 2 gene by the p53 pathway

Choi¹,

Cogdell²,

Feng³

et al. 2006

Cancer Biology & Therapy

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“…The ester linkage of a prodrug can be hydrolyzed by esterase that appears extensively in organs and tissues such as the blood, brain, liver, lung, heart, and etc. (Mistry and Houston, 1987;Nambu et al, 1987;Hussain et al, 1987). SDN was formulated in an oil solution because of its high lipophilicity and fulfilled the original design aim of a long-acting intramuscular preparation.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and in Vivo Evaluation of the Metabolism and Pharmacokinetics of Sebacoyl Dinalbuphine

Pao

Hsiong

et al. 2004

Drug Metab Dispos

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ABSTRACT:A diester prodrug of nalbuphine, sebacoyl dinalbuphine (SDN), and its long-acting formulation are currently being developed to prolong the duration of nalbuphine. A comparative in vitro hydrolysis study was conducted for SDN in rat, rabbit, dog, and human blood. Both SDN and nalbuphine in blood or plasma were measured by high-performance liquid chromatography. The hydrolysis rates of SDN in blood were ranked as follows: rat > rabbit > human > dog. The rapid formation of nalbuphine in the blood accounted for almost 100% of the prodrug, which supported the contention that nalbuphine is the major metabolite after SDN hydrolysis. The hydrolysis profiles of SDN were similar both in plasma and in red blood cells when compared in the blood. In vitro release results of SDN long-acting formulation showed that the rate-limited step of SDN hydrolysis to nalbuphine in blood is the penetration of SDN from oil into the blood. After intravenous administration of SDN in sesame oil into rats, nalbuphine quickly appeared in plasma and, thereafter, exhibited monoexponential decay. Pharmaceutical dosage forms affecting the drug disposition kinetics were demonstrated after intravenous administration. The AUC of nalbuphine was significantly higher and clearance was significantly lower, without changes in the t 1/2 of nalbuphine after intravenous dosing of SDN in sesame oil when compared with that of intravenous dosing with nalbuphine HCl in rats. Overall, these results suggest that SDN fulfilled the original pro-soft drug design in which the prodrug can rapidly metabolize to nalbuphine, and no other unexpected compounds were apparent in the blood.Esters have been the most common approach for prodrug development, because ester linkage of prodrugs tends to be converted efficiently to the active species through wide variability of esterase in the organs and tissues (Williams, 1985;Leinweber, 1987). The ester prodrugs apparently show that the safety and pharmacological actions of prodrugs seem to be the same as those for the parent compound (He et al., 1999;Ishikawa, 1999;Noble and Goa, 1999;Doucette and Aoki, 2001;Beaumont et al., 2003;Fischer et al., 2003). Nalbuphine is a potent -receptor agonist, -receptor antagonist analgesic with relatively low side effects (Jasinski and Mansky, 1972;Beaver and Feise, 1978). However, its short elimination half-life results in frequent injections for control of moderate to severe pain in clinical cases (Lo et al., 1987). SDN is a novel synthetic diester prodrug of nalbuphine designed to have high lipophilicity that consequently prolongs the duration of nalbuphine after intramuscular injection (Fig. 1).A successfully designed prodrug should not only be well absorbed, but should also metabolize primarily and readily to its active moiety. The prodrug should fulfill several criteria as proposed by Bodor (1984). Basically, no unexpected compound should be formed in vivo. Red blood cells and plasma are known to contain esterase (Leinweber, 1987;Cossum, 1988). In this study, SDN was examined for i...

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Enzymatic hydrolysis of haloperidol decanoate and its inhibition by proteins

Cited by 23 publications

References 14 publications

Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media

Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media

Transcriptional activation of the carboxylesterase 2 gene by the p53 pathway

In Vitro and in Vivo Evaluation of the Metabolism and Pharmacokinetics of Sebacoyl Dinalbuphine

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