Prodrugs soluble

Fosphenytoin Fosphenytoin is a water-soluble, phospho-ester prodrug of phenytoin that is rapidly converted to phenytoin in the body. It is compatible with most IV solutions and is well tolerated as an IM injection, even with the large volumes associated with loading doses (20 to 30 mL).19 It is dosed in phenytoin equivalents (PE), and it can be infused three times as fast as phenytoin, up to 150 mg PE/minute. The loading dose for patients not taking phenytoin is 15 to 20 mg PE/kg. It can be an advantage to use IM fosphenytoin when IV access cannot be obtained immediately and in patients with poor venous access. Although it has fewer cardiovascular side... 

D Fleisher, R Bong, BH Stewart. Improved oral drug delivery Solubility limitations overcome by the use of prodrugs. Adv Drug Deliv Rev 19 115-130, 1996. 

The ability of NB-355 to stimulate locomotor activity and induce dyskinesia in MPTP-treated squirrel monkeys was studied (MPTP induces parkinsonism) [9], NB-355 was similar to L-dopa in stimulating locomotor activity. Furthermore, NB-355 induced less severe dyskinesia than was seen with L-dopa. Some other prodrugs of L-dopa include short-chain alkyl esters (methyl, ethyl, isopropyl, butyl, hydroxypropyl, and hydroxybutyl) intended for rectal absorption [10], These esters of L-dopa have high water solubility (>600 mg/mL). Initial bioavailability studies indicated that all of these esters, with the exception of the hydroxypropyl ester, resulted in significantly greater bioavailability than that obtained with L-dopa itself. However, given the high level of esterase activity in the small intestine, the use of these compounds is limited to rectal administration. 

Acidic compounds with N—H bonds such as amides, carbamates, and hydan-toins, may be transformed to /V-rnannich bases to form oral prodrugs [2], These prodrugs are generally made by reacting an amide, carbamate, or hydantoin with formaldehyde and a primary or secondary aliphatic or aromatic amine (Fig. 4). The (V-mannich prodrugs tend to have better physicochemical properties than the parent compounds. The derivatives may have increased water solubility, dissolution rate, and/or lipophilicity. 

SA Varia, S Schuller, KB Sloan, VJ Stella. Phenytoin prodrugs III Water-soluble prodrugs for oral and/or parenteral use. J Pharm Sci 73(8) 1068-1073, 1984. 

Y Yumiko, RD Roberts, VJ Stella. Low-melting phenytoin prodrugs as alternative oral delivery modes for phenytoin A model for other high-melting sparingly water-soluble drugs. J Pharm Sci 72(4) 400-405, 1983. 

Limited oral drug bioavailability may be explained by poor membrane permeability, low aqueous solubility in gastrointestinal fluids, or extensive first-pass metabolism in the gastrointestinal tract or liver. Successful lipophilic prodrugs... 

The methylprednisolone suleptanate 208b, the water-soluble prodrug of the methylprednisolone corticosteroid 208a, has been labelled with 14C exclusively at the carboxamide carbon175 which was found to be metabolically stable with no loss of 14CC>2 after administration to test animals and man. 

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

Beside the MMFO mediated (phase I) reactions there are a few other major reactions that are worthy of note. The two major ones involve ester hydrolysis and alcohol and aldehyde dehydrogenases. All mammalian species have an extensive ability to hydrolyze the ester bond. The products of the reactions then can go on to be further metabolized. In the pharmaceutical industry, this property has been utilized to synthesize prodrugs that is, chemicals that have desirable pharmaceutical properties (generally increased water solubility) that are not converted to their active moiety until hydrolyzed in the body. 

Y Hamada, J Ohtake, Y Sohma, T Kimura, Y Hayashi, Y Kiso. New water-soluble prodrugs of HIV protease inhibitors based on 0—>N intramolecular acyl migration. Bioorg Med Chem 10, 4155, 2002. 

Many therapeutic agents are administered in a chemically modified form to improve features such as their solubility characteristics, ease of administration and bioavailability (Bowman and Rand, 1988). Such a prodrug must be designed to break down in vivo to release the active drug, sometimes at a... 

He X, Sugawara M, Kobayashi M, Takekuma Y, Miyazaki K (2003) An in vitro system for prediction of oral absorption of relatively water-soluble drugs and ester prodrugs. Int J Pharm 263 35 14... 

Careful prodrug design is required to minimize the number of proposed candidates and maximize the explored space of physicochemical and pharmacokinetic properties. The ability to predict target properties (e.g., solubility, extent of absorption, and rate of activation) is a major need in rational prodrug design, but global quantitative models simply do not exist, despite... 

As far as molecular properties are concerned, a first issue is the physicochemical profile of the prodrug candidate and its adequacy within the goals of the project. Some physicochemical properties can be calculated or estimated at the design stage, but experimental verification cannot be omitted. For other properties, such as solubility, quantitative predictions are more difficult and experimental assessment is mandatory. 

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