Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile

Abstract

Summary Etoposide phosphate is a water-soluble prodrug of etoposide. It was expected that this prodrug could be used to overcome the solubility limitations and erratic bioavailability of oral etoposide. To investigate the possibility of prodrug conversion to etoposide within the gastrointestinal lumen, etoposide phosphate was dissolved in water and incubated with human gastric juice or human bile in vitro. Samples were collected during 150 min and analysed for etoposide concentration with high-performance liquid chromatography. Conversion of prodrug to etoposide during incubation with gastric juice was negligible. There was significant conversion during incubation with bile at pH 7-8. The percentage of prodrug converted to etoposide at pH 8 after 60 min was 78 ± 18% (mean ± S.D.) for a 0.1 mg ml-' prodrug solution and 36 ± 26% for 0.5 mg ml-'. At pH 7, after 60 min 22% of prodrug was converted to etoposide when incubated at 0.1 mg ml-' and 10% at 0.5 mg ml-'. No conversion was found after inactivation of alkaline phosphate (AP) by overnight heating of bile at 650C or by the addition of disodium edetate to the bile. In conclusion, because of AP in bile, variable conversion of etoposide phosphate to etoposide can be expected within the intestinal lumen after oral administration. This could have important pharmacokinetic consequences.

A Highly Efficient Approach To Construct (epi)-Podophyllotoxin-4-O-glycosidic Linkages as well as Its Application in Concise Syntheses of Etoposide and Teniposide

“…This situation can be attributed to either the lack of an efficient glycosylation method specific for (epi)-podophyllotoxin 4-OH acceptors (for direct glycosylation protocol) or the relatively low glycosylation capacity of aryltetralin 4-OHs as glycosylation donors (for reverse glycoylation protocol). In constrast, the continuing emergence of aryltetralin 4-O-glycosides such as etopophos 7 and NK-611 8 with more promising pharmaceutical applications than etoposide and teniposide, as well as the incompletely understood functional mechanism of etoposide and teniposide, calls for a highly efficient method to construct the pivotal aryltetralin 4-O-glycosidic linkages. The challenges associated with aryltetralin 4-O-glycosidic linkage construction mainly originate from the acid sensitivity of benzylic aryltetralin 4-OHs and base vulnerability of the trans-fused B/C ring architecture of (epi)-podophyllotoxins.…”

Novel “Reverse Kahne-Type Glycosylation”: Access to O-, N-, and C-Linked Epipodophyllotoxin Conjugates

“…Its clinical success, as well as its incompletely understood mechanism of action, have stimulated interest in structural modification of the drug. Several congeners with altered carbohydrate sectors have emerged as promising drug candidates, including etopophos ( 2 ), NK-611 ( 3 ), TOP-53 ( 4 ), NPF ( 5 ), and GL-331 ( 6 ) (Figure ) 1 Epipodophyllotoxin conjugates with anticancer activity. …”

The Catalytically Lignan-Activation-Based Approach for the Synthesis of (epi)-Podophyllotoxin Derivatives

“…CH 2 Cl 2 was added to dilute the reaction mixture and the resulting solution was washed with water and saturated brine, successively. Evaporation and concentration under reduced pressure gave a residue which was further purified by silica gel chromatography (petroleum ether/ethyl acetate (PE/EA) = 3:1) to afford 4 (4.8 g, 97%) as a white solid: [α] D 25 = −169.1 (c 1.0, CHCl 3 ); 1 (epi)-Podophyllotoxin 4-O-ortho-Cyclopropylethynylbenzoate (5). A similar procedure as that used for the synthesis of 4 was applied to get 5 from 2 (495 mg, 88%) as a white solid: [α] D 25 = −50.8 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (dd, J = 1.2, 8.0 Hz, 1 H), 7.49 (dd, J = 1.6, 8.0 Hz, 1 H), 7.45 (td, J = 1.6, 7.2 Hz, 1 H), 7.33 (td, J = 1.6, 8.0 Hz, 1 H), 7.00 (s, 1 H), 6.58 (s, 1 H), 6.46 (d, J = 3.6 Hz, 1 H), 6.32 (s, 2 H), 6.00 (d, J = 1.2 Hz, 1 H), 5.96 (7).…”

“…In addition, the demand is further intensified by the incompletely understood working mechanism of (E)-PPT derivatives . Based on conventional derivatization methods, many pharmaceutically promising compounds such as NK-611, etopophos, TOP-53, and NPF have been discovered (Figure ).…”

“…H NMR (400 MHz, C 5 D 5 N) δ 7.33 (s, 1 H), 6.81 (s, 1 H), 6.79 (s, 2 H), 5.96 (s, 2 H), 5.71 (s, 1 H), 5.05 (d, J = 4.0 Hz, 1 H),5.046 (d, J = 7.6 Hz, 1 H), 4.90−4.86 (m, 2 H), 4.72 (dd, J = 8.8, 10.8 Hz, 1 H), 4.38−4.33 (m, 2 H), 4.07 (t, J = 9.2 Hz, 1 H), 3.77 (s, 6 H), 3.75−3.60 (m, 4 H), 3.30−3.24 (m, 2 H), 1.43 (d, J = 4.8 Hz, 3 H); 13 C NMR (100 MHz, C 5 D 5 N) δ 175.1, 148.6, 148.4, 147.2, 137.0, 133.3, 130.3, 130.1, 110.4, 109.6 (2 C), 105.0, 101.8, 99.6, 81.9, 74.1, 73.4, 68.4, 68.3, 67.2, 59.0, 56.3, 44.1, 41.7, 38.1, 20.5; HRMS (ESI-TOF) m/z: [M + H] + calcd for C 29 H 34 NO 12 588.2076, found 588.2068. NK-611 (3).…”