Pilocarpine Prodrugs II. Synthesis, Stability, Bioconversion, and Physicochemical Properties of Sequentially Labile Pilocarpine Acid Diesters

Bundgaard, Hans; Falch, Erik; Larsen, Claus; Mosher, Gerold L.; Mikkelson, Thomas J.

doi:10.1002/jps.2600750811

Cited by 69 publications

(17 citation statements)

References 14 publications

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“…to eliminate the high peak concentrations of pilocarpine in the eye and to prolong its duration of action (4)(5)(6). In the present study, administration of 14.3% (1/7) of the pilocarpine dose as a prodrug ((),()* -dtproptonyM 1,4-xylylene) bispilocarpate) decreased the peak miotic intensity of the solution and increased the time to reach the peak, but did not significantly affect values for the area under the miosis versus time curves (AUC).…”

Section: Discussionmentioning

confidence: 99%

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Sulfobutyl Ether β-Cyclodextrin (SBE-β-CD) in Eyedrops Improves the Tolerability of a Topically Applied Pilocarpine Prodrug in Rabbits

Järvinen¹,

Järvinen²,

Urtti³

et al. 1995

Journal of Ocular Pharmacology and Therapeutics

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The effects of a novel, modified p-cyclodextrin (SBE4-p-CD; a variably substituted sulfobutyl ether with an average degree of substitution of four) on eye irritation and miotic response of an ophthalmically applied pilocarpine prodrug, 0,0'-dipropionyl-(l,4-xylylene) bispilocarpate, in albino rabbits were studied. Compared to the commercial pilocarpine eyedrop solution (163 mM, equivalent to 3.4% pilocarpine), 12-24 mM pilocarpine prodrug solutions (equivalent to 0.5 -1.0% pilocarpine, respectively) decreased peak miotic intensity (I max ) and increased the time to reach peak (t max ), but did not significantly affect values for the area under the miosis versus time curves (AUC), i.e. 12 -24 mM pilocarpine prodrug appeared to be equivalent to 163 mM pilocarpine. Ocularly applied 12-24 mM pilocarpine prodrug solutions, however, were more irritating than a commercial pilocarpine eyedrop solution. Coadministered SBE4-p-CD significantly decreased the eye irritation of the pilocarpine prodrug solutions. Coadministered SBE4-P-CD did not affect the miotic response of prodrug solution when the molar ratio of SBE4-p-CD to prodrug was low. However, increasing the molar ratio of SBE4-p-CD to prodrug decreased the I max and AUC values. The results show that eye irritation of the pilocarpine prodrug is prevented by levels of SBE4-P-CD that do not affect the apparent ocular absorption of the prodrug.

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Section: Discussionmentioning

confidence: 99%

“…However, duration of action for ophthalmic pilocarpine is short and its ocular bioavailability is only 0.1-3% of the instilled pilocarpine dose (1)(2)(3). Thus, the prodrug technique has been applied to improve the ocular delivery of pilocarpine (4)(5)(6). 0,0'-Dipropionyl-(l,4-xylylene) bispilocarpate ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Sulfobutyl Ether β-Cyclodextrin (SBE-β-CD) in Eyedrops Improves the Tolerability of a Topically Applied Pilocarpine Prodrug in Rabbits

Järvinen¹,

Järvinen²,

Urtti³

et al. 1995

Journal of Ocular Pharmacology and Therapeutics

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“…The prodrug approach has been utilized to enhance the ocular delivery of pilocarpine [43][44][45][46]. Pilocarpine is a widely used topical mitotic agent used to control the elevated intraocular pressure associated with glaucoma, but the drug itself presents significant delivery problems.…”

Section: A the Prodrug Approachmentioning

confidence: 99%

“…For the above reason, a number of lipophilic alkyl and arylalkyl esters of pilocarpic acid were synthesized [43][44][45][46] and evaluated as prodrugs of pilocarpine. The results obtained suggested that the pilocarpic acid esters may be potentially useful prodrugs with enhanced drug delivery and bioavailability properties, especially when further derivatized to give non-labile, easily formulated pilocarpic acid diesters that convert readily to the parent drug in vivo (Figure 1) [43,44].…”

Section: A the Prodrug Approachmentioning

confidence: 99%

“…The results obtained suggested that the pilocarpic acid esters may be potentially useful prodrugs with enhanced drug delivery and bioavailability properties, especially when further derivatized to give non-labile, easily formulated pilocarpic acid diesters that convert readily to the parent drug in vivo (Figure 1) [43,44]. In aqueous solution the esters undergo a quantitative and apparent specific base-catalyzed lactonization to pilocarpine [50].…”

Section: A the Prodrug Approachmentioning

confidence: 99%

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Phase I and Phase II Ocular Metabolic Activities and the Role of Metabolism in Ophthalmic Prodrug and Codrug Design and Delivery

Al-Ghananeem

Crooks

2007

Molecules

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While the mammalian eye is seldom considered an organ of drug metabolism, the capacity for biotransformation is present. Compared to the liver, the metabolic capabilities of the eye are minuscule; however, phase I and phase II metabolic activities have been detected in various ocular structures. The careful consideration of ocular tissue metabolic processes within the eye has important implications for controlling the detoxification of therapeutic agents and for providing the potential for site-specific bio-activation of certain drug molecules, thus enabling significant improvements in drug efficacy and the minimization of side-effect from either local or systemic drug delivery to the eye. Knowledge of these processes is important to prodrug and codrug development and to researchers involved in the design, delivery and metabolism of ophthalmic drugs. This present article reviews the progress in ocular prodrug and codrug design and delivery in light of ocular metabolic activities.

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Principles of Drug Metabolism

Testa

Soine

2003

Burger's Medicinal Chemistry and Drug Discovery

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The focus of this chapter is mainly on drug metabolism reactions and connected information of significance to medicinal chemists. The types, selectivities, and consequences of drug metabolism are presented in the introduction. Oxidoreductases are discussed in the next section, together with a systematic and extensive treatment of the chemical groups they target and the functionalization reactions they catalyze. Particular attention is paid to cytochromes P450 and their multiplicity, specificities, and relative importance. Section 3 is dedicated to the transferases and the conjugation reactions they catalyze, e.g., glucuronidation and glutathione conjugation. The various biological factors influencing drug metabolism are examined in Section 4. These are subdivided into interindividual factors (that depend on the genome) and intraindividual factors (that can vary with time or because of external influences). The last section, which is particularly close to the interests of medicinal chemists, discusses structure‐metabolism relationships, prodrug design, and toxophoric groups.

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Pilocarpine Prodrugs II. Synthesis, Stability, Bioconversion, and Physicochemical Properties of Sequentially Labile Pilocarpine Acid Diesters

Cited by 69 publications

References 14 publications

Sulfobutyl Ether β-Cyclodextrin (SBE-β-CD) in Eyedrops Improves the Tolerability of a Topically Applied Pilocarpine Prodrug in Rabbits

Sulfobutyl Ether β-Cyclodextrin (SBE-β-CD) in Eyedrops Improves the Tolerability of a Topically Applied Pilocarpine Prodrug in Rabbits

Phase I and Phase II Ocular Metabolic Activities and the Role of Metabolism in Ophthalmic Prodrug and Codrug Design and Delivery

Principles of Drug Metabolism

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