Testosterone 17β‐N,N‐Dimethylglycinate Hydrochloride: A Prodrug with a Potential for Nasal Delivery of Testosterone

Hussain, Anwar; Al-Bayatti, Ansam A.; Dakkuri, Adnan; Okochi, Kazuhiro; Hussain, Munir

doi:10.1002/jps.10083

Cited by 21 publications

(9 citation statements)

References 8 publications

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“…Furthermore, their nasal administration resulted in a rapid and complete absorption to the systemic circulation, where quick conversion to L-Dopa takes place. Similar results were obtained for testosterone which is also poorly water-soluble (127).…”

Section: Prodrugssupporting

confidence: 84%

Intranasal Drug Delivery: How, Why and What for?

2009

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Over the recent decades the interest in intranasal delivery as a non-invasive route for drugs is increased. Since the nasal mucosa offers numerous benefits as a target tissue for drug delivery, a wide variety of therapeutic compounds may be administered intranasally for topic, systemic and central nervous system action. We have, herein, outlined the relevant aspects of nasal anatomy, physiology and histology, and the biological, physicochemical and pharmaceutical factors that must be considered during the process of discovery and development of nasal drugs as well as in their incorporation into appropriate nasal pharmaceutical formulations. _______________________________________________________________________________________

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Section: Prodrugssupporting

confidence: 84%

Intranasal Drug Delivery: How, Why and What for?

2009

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“…Thus, we first assessed the ability of four different sex steroid hormones to alter P. aeruginosa alginate production. The tested compounds varied in polarity and included the synthetic hormone ethinylestradiol (EE2) (logP, 4.15) ( 18 ) (least polar), testosterone (T) (logP, 3.30) ( 19 ), the pregnancy-related estrogen estriol (E3) (logP, 2.45) ( 20 ), and a water-soluble synthetic and hydrophilic derivative of testosterone, TSDG.HCl (logP, 2.40) ( 21 ) (most polar) ( Fig. 1A ).…”

Section: Resultsmentioning

confidence: 99%

Sex Steroids Induce Membrane Stress Responses and Virulence Properties in Pseudomonas aeruginosa

Vidaillac

Yong

Aschtgen

et al. 2020

mBio

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Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases, including cystic fibrosis. This results in long-term persistence, poorer clinical outcomes, and limited therapeutic options. In this study, we demonstrate that at physiological concentrations, sex steroids, including testosterone and estriol, induce membrane stress responses in P. aeruginosa. This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting in vivo persistence of the bacteria. The steroid-induced P. aeruginosa response correlates with the molecular polarity of the hormones and membrane fluidic properties of the bacteria. This novel mechanism of interaction between sex steroids and P. aeruginosa explicates the reported increased disease severity observed in females with cystic fibrosis and provides evidence for the therapeutic potential of the modulation of sex steroids to achieve better clinical outcomes in patients with hormone-responsive strains. IMPORTANCE Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection.

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“…One strategy often employed for improvement in oral bioavailability is masking a compound’s polar ionizable groups via a prodrug approach. The idea is that less polar prodrugs will have enhanced intestinal permeability, and upon absorption, they will be cleaved to the active drug via plasma or liver enzymes. − Notably, prodrug strategies are common in drug development; about 10–12% of the approved worldwide drugs are prodrugs, and of these, most are primarily designed with an objective to enhance the permeability of the parent drug . Specifically, drugs containing carboxylates, phosphate, phosphonate, or phosphinate functional group encounter permeability challenges due to the anionic charge at nearly all physiological pH, making them highly polar and requiring their delivery as ester- or amide-based prodrugs. , This strategy has been successfully implemented for the approved prodrugs such as adefovir dipivoxil [bis-(pivaloyloxymethyl) ester of adefovir] and tenofovir disoproxil [bis-(isopropyloxycarbonyloxymethyl) ester of tenofovir], where a 4- and 7-fold enhancement in oral bioavailability was observed, respectively. − …”

Section: Discussionmentioning

confidence: 99%

Enhanced Oral Bioavailability of 2-(Phosphonomethyl)-pentanedioic Acid (2-PMPA) from its (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL)-Based Prodrugs

et al. 2019

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2-(Phosphonomethyl)-pentanedioic acid (2-PMPA) is a potent (IC50 = 300 pM) and selective inhibitor of glutamate carboxypeptidase II (GCPII) with efficacy in multiple neurological and psychiatric disease preclinical models and more recently in models of inflammatory bowel disease (IBD) and cancer. 2-PMPA (1), however, has not been clinically developed due to its poor oral bioavailability (<1%) imparted by its four acidic functionalities (c Log P = −1.14). In an attempt to improve the oral bioavailability of 2-PMPA, we explored a prodrug approach using (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL), an FDA-approved promoiety, and systematically masked two (2), three (3), or all four (4) of its acidic groups. The prodrugs were evaluated for in vitro stability and in vivo pharmacokinetics in mice and dog. Prodrugs 2, 3, and 4 were found to be moderately stable at pH 7.4 in phosphate-buffered saline (57, 63, and 54% remaining at 1 h, respectively), but rapidly hydrolyzed in plasma and liver microsomes, across species. In vivo, in a single time-point screening study in mice, 10 mg/kg 2-PMPA equivalent doses of 2, 3, and 4 delivered significantly higher 2-PMPA plasma concentrations (3.65 ± 0.37, 3.56 ± 0.46, and 17.3 ± 5.03 nmol/mL, respectively) versus 2-PMPA (0.25 ± 0.02 nmol/mL). Given that prodrug 4 delivered the highest 2-PMPA levels, we next evaluated it in an extended time-course pharmacokinetic study in mice. 4 demonstrated an 80-fold enhancement in exposure versus oral 2-PMPA (AUC0–t : 52.1 ± 5.9 versus 0.65 ± 0.13 h*nmol/mL) with a calculated absolute oral bioavailability of 50%. In mouse brain, 4 showed similar exposures to that achieved with the IV route (1.2 ± 0.2 versus 1.6 ± 0.2 h*nmol/g). Further, in dogs, relative to orally administered 2-PMPA, 4 delivered a 44-fold enhanced 2-PMPA plasma exposure (AUC0–t for 4: 62.6 h*nmol/mL versus AUC0–t for 2-PMPA: 1.44 h*nmol/mL). These results suggest that ODOL promoieties can serve as a promising strategy for enhancing the oral bioavailability of multiply charged compounds, such as 2-PMPA, and enable its clinical translation.

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Testosterone 17β‐N,N‐Dimethylglycinate Hydrochloride: A Prodrug with a Potential for Nasal Delivery of Testosterone

Cited by 21 publications

References 8 publications

Intranasal Drug Delivery: How, Why and What for?

Intranasal Drug Delivery: How, Why and What for?

Sex Steroids Induce Membrane Stress Responses and Virulence Properties in Pseudomonas aeruginosa

Enhanced Oral Bioavailability of 2-(Phosphonomethyl)-pentanedioic Acid (2-PMPA) from its (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL)-Based Prodrugs

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