Serum-Catalyzed Hydrolysis of Metronidazole Amino Acid Esters

Cho, Moo J.; Haynes, Lynn C.

doi:10.1002/jps.2600740817

Cited by 20 publications

(6 citation statements)

References 9 publications

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“…In vivo, the glycyl ester, 4, as a 1% borate eyedrop solution (pH 5.7), demonstrated efficacy against H8V-1 keratitis in the rabbit. However, solutions of 4 at pH 7.4 and physiological temperature were 50% hydrolyzed after 4 h, and completely hydrolyzed after 1 d. Instability has been a common shortcoming of amino acid esters (Kovach et al, 1981;Cho and Haynes, 1985;Johnson et al, 1985).…”

Section: Acyclovirmentioning

confidence: 99%

Amino Acid Ester Prodrugs of Acyclovir

Beauchamp

Orr

Miranda

et al. 1992

Antivir Chem Chemother

202

138

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SummaryEighteen amino acid esters of the antiherpetic drug, acyclovir, were synthesized as potential prodrugs for oral administration. The esters were examined for in vitro antiviral activity against herpes simplex virus Type 1 (HSV-1). They were found to have less potency than the parent compound. Their efficiencies as prodrugs were evaluated in rats by measuring the urinary recovery of acyclovir. Ten prodrugs produced greater amounts of the parent drug in the urine. The L-amino acid esters were better prodrugs than the corresponding D-or D,L-isomers, suggesting the involvement of a stereoselective transporter. The L-valyl ester, 256U87, was the best prodrug. Sixty three per cent of its administered dose was excreted as acyclovir in the urine, a considerable improvement over acyclovir itself, for which this value was 19%. Since 256U87 was stable in aqueous solutions, its conversion to acyclovir in vivo was probably enzyme catalyzed. This L-valyl ester prodrug of acyclovir is now undergoing clinical evaluation.

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Section: Acyclovirmentioning

confidence: 99%

Amino Acid Ester Prodrugs of Acyclovir

Beauchamp

Orr

Miranda

et al. 1992

Antivir Chem Chemother

202

138

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“…A third type of water-soluble ester prodrug had an ionizable amino function in the acid moiety, which revealed facile hydrolysis in human plasma as illustrated by propacetamol, 4-(acetamido) phenyl diethylaminoacetate HCl salt, which is an injectable water soluble form of paracetamol currently approved by the European Pharmacopoeia 2000. Application of this prodrug type on metronidazole has been reported (Bundgaard et al 1984a(Bundgaard et al , b, 1989Cho & Haynes 1985 ;Jensen et al 1990). This type of water-soluble ester prodrug was investigated mostly as the hydrochloride salt but unfortunately it showed high instability in aqueous solutions (Bundgaard et al 1989 ;Jensen et al 1990).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility

Mahfouz

Hassan

2001

Journal of Pharmacy and Pharmacology

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A series of amino acid esters (3a-e) have been synthesized and evaluated as potential prodrugs of metronidazole with the aim of improving aqueous solubility and therapeutic efficacy. The aqueous solubility and the lipophilicity (expressed as the log P value) of metronidazole and its esters were investigated. In general the prodrugs revealed enhanced water solubility compared with metronidazole. N,N-diethylglycinate hydrochloride (3a) and 4-ethylpiperazinoacetate (3e) derivatives displayed higher aqueous solubility, which exceeded that of the parent drug by factors of approximately 140 and 100, respectively. All the esters revealed lower log P values than metronidazole except for the 4-phenylpiperazinoacetate derivative (3f), which was 6.5-times more lipophilic than metronidazole. The hydrolysis kinetics of the esters were studied in aqueous phosphate buffer (pH 7.4) and 80% human plasma at 37 degrees C. In all cases the hydrolysis followed pseudo-first-order kinetics and resulted in a quantitative reversion to metronidazole as evidenced by HPLC analysis. The prodrugs exhibited adequate chemical stability (half-life, t1/2, 4-16 h) in aqueous phosphate solution of pH 7.4. In 80% human plasma they were hydrolysed within a few minutesto metronidazole. The esters 3d (methylpiperazinoacetate derivative) and 3f were exempted since their t1/2 values were approximately 2.5 and 8.5 h, respectively. A comparative pH-rate profile study of N,N-diethylglycinate hydrochloride (3a) and 4-ethyl-piperazinoacetate (3e) derivatives in aqueous buffer solution over the pH range 2.2-10 was investigated. The results indicated that 3a showed marked stability at pH 2-6 followed by accelerated hydrolysis at pH 7.4. The basic ester 3e was found to be less stable at lower pH values but exhibited comparative stability at physiological pH. Moreover, in-vivo experiments in rabbits revealed a higher metronidazole plasma level with sustained release characteristics within the prodrug-treated animals (10- and 2.5-fold) as compared with the parent drug-treated group. In conclusion, the designed amino acid esters 3a and 3c-e might be considered as good candidates for water-soluble prodrug forms of metronidazole.

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“…Today, a more frequently employed method for improving the solubility is attaching a solubilizing moiety, such as amino acid, which is cleaved by an endogenous enzyme subsequent to absorption, therefore, regenerating the active parent molecule 3 . Amino acid prodrugs have been investigated in the past as promoieties to improve the aqueous solubility of various alcohol and amine drugs [4][5][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Solubility and solution stability studies of different amino acid prodrugs of bromhexine

Aggarwal

Gupta²

2012

Drug Development and Industrial Pharmacy

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Solubility studies and partition coefficient values indicated that the synthesized prodrug, 2-N-L-alanyl-bromhexine hydrochloride, was least lipophilic as compared to other synthesized prodrugs. Solution stability studies showed that this prodrug undergo minimum hydrolysis at 37°C. So, it is concluded that 2-N-L-alanyl-bromhexine hydrochloride exhibits better solubility and stability as compared to other synthesized prodrugs.

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Serum-Catalyzed Hydrolysis of Metronidazole Amino Acid Esters

Cited by 20 publications

References 9 publications

Amino Acid Ester Prodrugs of Acyclovir

Amino Acid Ester Prodrugs of Acyclovir

Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility

Solubility and solution stability studies of different amino acid prodrugs of bromhexine

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