Volume prodrugs

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... 

Steffansen, B., Prodrugs, in Encyclopedia of Pharmaceutical Technology, volume 13. Swarbrick, J., Boyiand,... 

Volume V Prodrugs Challenges and Rewards, Parts 1 and 2 V.J. Stella, R.T. Borchardt, M.J. Hageman, R. Oliyai, H. Maag, J.W. Tilley... 

Prodrugs, which occupy a significant position in the scope of the present volume, were defined and discussed in Chapt. 1. In addition to this chapter, prodrugs activated by reactions of hydrolysis receive further attention in Chapt. 4, 6, 9, and 11. 

It should also be noted that the activation of a mechanism-based inhibitor by its target enzyme is, formally, an example of metabolic activation. However, there is a clear distinction between the activation of a mechanism-based inhibitor described above and the metabolic activation of a prodrug. In the latter case, an inactive precursor is metabolized in the body (either chemically or enzymatically) to metabolites that possess the desired activity. For example. Acyclovir (3a) must be metabol-ically converted to the triphosphate (3b) and released into the medium before it will inhibit viral DNA polymerase. Further discussion on prodrugs may be found in volume 2, chapter 14. 

After intravenous administration of etoposide 150 mg/ m, the peak plasma concentration averages 20 micro-grams/ml and the half-life 7.1 hours. Drug clearance and distribution volume are about 16 ml/minute/m and 17 1/ m (6,7,74). With respect to plasma concentrations of etoposide, intravenous etoposide phosphate is equivalent to intravenous etoposide with conventional or intensified dose schedules (75-79). After intravenous administration, the prodrug etoposide phosphate undergoes rapid hydrolysis catalysed by alkaline phosphatase this conversion is linear even at high intravenous doses of 1200 mg/m infused over 2 hours on days 1 and 2. 

These substances metabolized within the CNS illustrate well one of the difficulties that may be encountered with prodrug kinetics. The prodrug may follow an ADME pattern perfectly well described by its systemic availability, volume of distribution, and both hepatic and renal clearances, but still have a pharmacological effect whose dependency on blood kinetics is only indirect. This is particularly true if the drug must diffuse through the blood-brain barrier, and is then metabolized by enzyme systems different from those found in the liver. 

Oral oseltamivir phosphate is absorbed rapidly and cleaved by esterases in the GI tract and liver to the active carboxylate. Low levels of the phosphate are detectable, but exposure is only 3 to 5% of that of the metabolite. The bioavailability of the carboxylate is estimated to be approximately 80%. The time to maximum plasma concentrations of the carboxylate is about 2.5 to 5 hours. Food does not decrease bioavailability but produces the risk of GI intolerance. After 75-mg doses, peak plasma concentrations average 0.07 pg/mL for oseltamivir phosphate and 0.35 pg/mL for the carboxylate. The carboxylate has a volume of disttibution similar to extracellular water. Broncho-alveolar lavage levels in animals and middle-ear fluid and sinus concentrations in humans are comparable with plasma levels. Following oral administtation, the plasma half-life of oseltamivir phosphate is 1 to 3 hours and that of the carboxylate ranges from 6 to 10 hours. Both the prodrug and active metabolite are eliminated primarily unchanged through the kidney. Probenecid doubles the plasma half-life of the carboxylate, which indicates tubular secretion by the anionic pathway. 

The articles contained in this volume include the interaction of alkaloids with neuroreceptors and ion channels, anthracyclines suited for antibody-directed enzyme prodrug therapy and metabolites from soilborne fungi. Several articles are concerned with bioactive natural products from marine sources. The other areas covered include natural products with polyene amide structures, potential hypoglycemic agents, biological activity of essential oils, bioactive saponins and biologically active diterpenoids. 

Several dinucleotide analogues have been reported as potential prodrugs of the 5 -monophosphates of biologically active nucleotides. These include the a-hydroxybenzylphosphonates of AZT (also see volume 27 in this series) (54), the benzyl phosphate triesters (55) and the 4-acyloxybenzyl phosphate triesters... 

Oral oseltamivir phosphate is absorbed rapidly (Table 49-3) and cleaved to the active carboxylate by esterases in the GI tract and liver. The bioavailability of the carboxylate is 80% food does not decrease bioavailability but reduces GI symptoms. The carboxylate has a volume of distribution similar to extracellular water. Both prodrug and active metabolite are eliminated primarily unchanged by the kidney. 

The parent compound has low oral bioavailability (<12%), whereas the dipivoxil prodrug is absorbed rapidly and hydrolyzed by esterases in the intestine and blood to adefovir. Adefovir bioavailability is 30-60%. Food does not affect bioavailability. Adefovir has low protein binding (<5%) and has a volume of distribution similar to body water (-0.4 L/kg). 

Dextran is generally used for medical purposes as an antithrombotic (antiplatelet), to reduce blood viscosity, and as a volume expander in anemia. " It has been found out that dextran can be degraded by the enzyme dextranase in the colon, and so a polymeric prodrug for colonic drug delivery based on dextran can be possibly designed. 

Another prodrug synthesis using a microfluidic reaction system is that of the antibiotic ciprofloxacin [10], A microreaction system developed by CPC systems (CYTOS) was used as a reaction apparatus. This system is the size of a videotape with a holdup of 1.8 ml. The high surface-to-volume ratio for the mixing section as well as for the temperature-controlled reaction channels allows heat transfer coefficients of up to 2,000 Wm K . The synthesis has demonstrated the potential for faster development, particularly in the preparation of relevant quantities for development studies, such as clinical trials, using the microreaction systems. 

The PPIs are prodrugs, activated by exposure to pHs less than 5. Once activated, the drugs bind irreversibly to the H+, K+- ATPase (the proton pump ) in the parietal ceU apical membrane, inhibiting its activity and decreasing gastric acid production by more than 95 %. The process is irreversible in that new enzyme needs to be produced to overcome the inhibition. PPIs have little effect on gastric acid volume and do not affect gastric motility. 

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