Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs

Heimbach, Tycho; Oh, Doo Man; Li, Lilian Y.; Rodrı́guez-Hornedo, Naı́r; Garcia, George A.; Fleisher, David

doi:10.1016/s0378-5173(03)00287-4

Cited by 51 publications

(32 citation statements)

References 20 publications

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“…The charged prodrug rapidly dissolves in the gastrointestinal lumen, but diffusion across biological membranes is limited meaning that dephosphorylation by intestinal alkaline phosphatase is required for intestinal uptake. Due to the lower solubility of the parent drug, a supersaturated solution may be generated, increasing the driving force for absorption 55, 56. Potential precipitation of the parent drug prior to intestinal uptake has been identified as one of the major pitfalls for the success of phosphate ester prodrugs 57.…”

Section: Supersaturating Drug Delivery Systems (Sdds)mentioning

confidence: 99%

Supersaturating Drug Delivery Systems: The Answer to Solubility-Limited Oral Bioavailability?

Brouwers

Brewster

Augustijns

2009

Journal of Pharmaceutical Sciences

827

623

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Section: Supersaturating Drug Delivery Systems (Sdds)mentioning

confidence: 99%

Supersaturating Drug Delivery Systems: The Answer to Solubility-Limited Oral Bioavailability?

Brouwers

Brewster

Augustijns

2009

Journal of Pharmaceutical Sciences

827

623

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“…RAL was only detected in serum from rats treated with RAL diphosphate. In addition, since RAL diphosphate was dephosphorylated by rat intestinal cytosol and microsome, but not by rat serum, the phosphate‐derivatives may be cleaved primarily during transportation in the intestine, which contains a high level of alkaline phosphatase,27 as reported previously for TAT‐59 17. Thus, the RAL prodrug was shown to improve the oral bioavailability of RAL.…”

Section: Discussionmentioning

confidence: 63%

“…As a result, higher doses must be administered to obtain an efficacy equivalent to that achieved with TAM 16. TAT‐59 was designed earlier as a phosphate ester antiestrogen prodrug and has shown improved oral bioavailability 17. If a prodrug is established for RAL, such a compound could increase the drug's antitumor potential, resulting in greater clinical benefit for breast cancer therapy and prevention.…”

mentioning

confidence: 99%

Increased antitumor potential of the raloxifene prodrug, raloxifene diphosphate

Okamoto

Suzuki

et al. 2008

Intl Journal of Cancer

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Raloxifene (RAL) significantly reduced the incidence of breast cancer in women at high risk of developing the disease. Unlike tamoxifen (TAM), an increased incidence of endometrial cancer was not observed in women treated with RAL. However, RAL, having two hydroxyl moieties, can be conjugated rapidly through phase II metabolism and excreted, making it difficult to achieve adequate bioavailability by oral administration in humans. As a result, higher doses must be administered to obtain an efficacy equivalent to that achieved with TAM. To improve oral bioavailability and antitumor potential, RAL diphosphate was prepared as a prodrug. RAL diphosphate showed several orders of magnitude lower binding potential to both ERa and ERb and weak antiproliferative potency on cultured human MCF-7 and ZR-75-1 breast cancer cells, as compared to RAL. However, RAL diphosphate has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL against both 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats and human MCF-7 breast cancer implanted in athymic nude mice. The RAL prodrug may provide greater clinical benefit for breast cancer therapy and prevention. ' 2008 Wiley-Liss, Inc.Key words: raloxifene; prodrug; breast cancer; antitumor Tamoxifen (TAM) is widely used as a first-line endocrine therapy for early-stage breast cancer patients with positive estrogen receptors (ERs) 1 and as a prophylactic agent for women at high risk of developing this disease. 2 However, besides the significant benefit, long-term administration of TAM has serious adverse effects, including causing endometrial cancer in women. [2][3][4][5] The carcinogenic effect is thought to involve initiation and/or promotion due to the DNA damage induced by TAM and its metabolites as well as its estrogenic action (reviewed in Refs. 6 and 7). Therefore, a safer alternative is required to diminish the side-effects and to increase clinical efficacy.Raloxifene (RAL) is used for treating osteoporosis. Recent clinical trials showed that RAL significantly reduced the incidence of breast cancer in women at high risk of developing the disease. 8 Unlike TAM, an increased incidence of endometrial cancer was not observed in women treated with RAL 9,10 although the drug retains a weak proliferative effect on the uterus in postmenopausal women. 11 The Food and Drug Administration (FDA) has just approved RAL for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. 12 However, since RAL has 2 hydroxyl moieties, the hydroxylated compound can be conjugated rapidly through phase II metabolism 13,14 and excreted. This makes it difficult to achieve adequate bioavailability by oral administration in humans. 15 As a result, higher doses must be administered to obtain an efficacy equivalent to that achieved with TAM. 16 TAT-59 was designed earlier as a phosphate ester antiestrogen prodrug and has shown improved oral bioavailability. 17 If a ...

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“…As such, it represents only one of several dimensions of a complex in vivo system. Reports have shown that including an absorptive component can alter the dynamic equilibrium between bioconversion, supersaturation, and absorption (Heimbach et al, 2003b;Brouwers et al, 2007;Bevernage et al, 2012). While this is a typical shortcoming of all fractional in vitro systems, the advantage of the rIALP turnover assay is that, when the right protein concentration is used, it provides a strong indication that cleavage is going to be insufficient or potentially very rapid in vivo.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Recombinantly Expressed Rat and Monkey Intestinal Alkaline Phosphatases: In Vitro Studies and In Vivo Correlations

et al. 2013

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Intestinal alkaline phosphatases (IALPs) are widely expressed in the brush border of epithelial cells of the intestinal mucosa. Although their physiologic role is unclear, they are very significant when it comes to the release of bioactive parent from orally dosed phosphate prodrugs. Such prodrugs can be resistant to cleavage by IALP, or alternatively undergo rapid cleavage leading to the release and precipitation of the less soluble parent. Because purified IALPs from preclinical species are not commercially available, and species differences have not been investigated to date, an effort was made to recombinantly express, purify, and characterize rat and cynomolgus monkey IALP (rIALP). Specifically, recombinant IALP (rIALP)-catalyzed cleavage of five prodrugs (fosphenytoin, clindamycin phosphate, dexamethasone phosphate, ritonavir phosphate, and ritonavir oxymethyl phosphate) was tested in vitro and parent exposure was assessed in vivo (rat only) following an oral dose of each prodrug. It was determined that the rate of phosphate cleavage in vitro varied widely; direct phosphates were more resistant to bioconversion, whereas faster conversion was observed with oxymethyl-linked prodrugs. Overall, the rat rIALPderived data were qualitatively consistent with in vivo data; prodrugs that were readily cleaved in vitro rendered higher parent drug exposure in vivo. Of the five prodrugs tested, one (ritonavir phosphate) showed no conversion in vitro and no in vivo parent exposure. Finally, the apparent K m values obtained for fosphenytoin and clindamycin phosphate in vitro suggest that IALP is not likely to be saturated at therapeutic doses.

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Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs

Cited by 51 publications

References 20 publications

Supersaturating Drug Delivery Systems: The Answer to Solubility-Limited Oral Bioavailability?

Supersaturating Drug Delivery Systems: The Answer to Solubility-Limited Oral Bioavailability?

Increased antitumor potential of the raloxifene prodrug, raloxifene diphosphate

Characterization of Recombinantly Expressed Rat and Monkey Intestinal Alkaline Phosphatases: In Vitro Studies and In Vivo Correlations

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