Prodrugs phosphate esters

SA Varia, VJ Stella. Phenytoin prodrugs VI In vivo evaluation of a phosphate ester prodrug of phenytoin after parenteral administration to rats. J Pharm Sci 73(8) 1087-1090, 1984. 

S. A. Varia, V. J. Stella, Phenytoin Prodrugs VI In vivo Evaluation of a Phosphate Ester Prodrug of Phenytoin after Parenteral Administration to Rats , J. Pharm. Sci. 1984, 73, 1087-1090. 

Taxol (paclitaxel) is a cytotoxic drug that has been shown to have potent antileukemic and tumor inhibitory properties. Taxol suffers from very poor water solubility (0.25 pg/mL), and hence, a few phosphate ester prodrugs of taxol have been synthesized. While great improvement of water solubility was achieved (>10 mg/mL), these prodrugs were resistant to degradation by alkaline phosphatase, probably due to hindered enzyme access, and no free taxol was formed [50],... 

Kim H, Kumari P, Lin CC, Nomeir AA (2002) Simultaneous high-performance liquid chromatographic determination of SCH 59884 (phosphate ester prodrug of SCH 56592), SCH 207962 and SCH 56592 in dog plasma. J Pharm Biomed Anal 27(l-2) 295-303... 

Juntunen, J., Jarvinen, T. and Niemi, R. (2005) In-vitro corneal permeation of cannabinoids and their water-soluble phosphate ester prodrugs. Journal of Pharmacy and Pharmacology, 57, 1153-1157. 

Figure 8.28 Water-soluble phosphate ester prodrug of phenytoin.

Fosphenytoin, the water-soluble phosphate ester of phenytoin, is a phenytoin prodrug. 

Phenytoin is a diphenyl-substituted hydantoin with the structure shown. It has much lower sedative properties than compounds with alkyl substituents at the 5 position. A more soluble prodrug of phenytoin, fosphenytoin, is available for parenteral use this phosphate ester compound is rapidly converted to phenytoin in the plasma. 

The physiochemical properties of noladin ether (164) were successfully improved by introducing a phosphate moiety to the structure. High water solubility and chemical stability, together with a rapid quantitative enzymatic hydrolysis in vitro and the ability to reduce lOP in vivo, prove that the phosphate esters (165) and (166) are promising prodrug candidates of end-ocannabinoid noladin ether (Figure 26). ... 

Oseltamivir came on the market in 2000 under the name of Tamiflu 36, which is the phosphate salt of the ethyl ester prodrug [86]. Oseltamivir phosphate is well absorbed in the G1 tract and can therefore be administered orally. Approximately 80% of an oral dose reaches... 

To increase the hydrophilicity of an agent, several different types of ester prodrugs have been used, including succinates, phosphates, and sulfonates. All arc ioni/ed at physiological pH and. therefore, increase the water. solubility of the agents, making them more suitable for parenteral or oral administration when high water solubility is desirable (Scheme 5-11). 

Phosphate esters, us prodrugs. 149, i49f Phosphocol. See Chromic phosphate P 32 Phosphodiesierasc 5 inhibitors, active sites of 29. 30f... 

On the other hand, formation of a prodrug such as a phosphate ester may increase hydrophilicity, thus enhancing solubility. For example, the solubility and dissolution rate of the 77-hydroxymethyl derivative of lomefloxacin is higher than those of the parent compound, and it can be converted readily back to the original molecule. Commonly used prodrugs are procaine penicillin metronidazole phosphate and chloramphenicol sodium succinate. 

Oseltamivir phosphate is an ethyl ester prodrug that lacks antiviral activity. Oseltamivir carboxylate has an antiviral spectrum and potency similar to that of zanamivir. It inhibits amantadine- and rimantadine-resistant influenza A viruses and some zanamivir-resistant variants. 

Chndamycin palmitate, an oral prodrug, is hydrolyzed rapidly in vivo. Its absorption is similar to clindamycin. The phosphate ester of clindamycin, given parenterally, also is rapidly hydrolyzed to the active parent compound. 

Tenofovir disoproxil is a prodrug in a manner similar to that of adefovir dipivoxil. In both cases, the phosphate esters are removed through the action of plasma esterase, leading in this case to tenofovir. 

---