Phenytoin bioavailability

Hall TG, Cuddy PG, Glass CJ, Melethil S. Effect of sucralfate on phenytoin bioavailability. Drug Intell Clin Pharm 1986 20(7-8) 607-ll. 

Sylvester RK, Lewis FB, Caldwell KC, Lobell M, Perri R, Sawchuk RA. Impaired phenytoin bioavailability secondary to cispladnum, vinblastine, and bleomycin. Tber... 

Carter BL, Garnett WR, PeUock JM, Stratton MA, HoweU JR. Effect of antacids ai phenytoin bioavailability. TherDrugMonit( 9% ) 3,333—40. 

Gatti G, Bartoli A, Marchiselli R, Michelucci R, Tassinari CA, Pisani F, Zaccara G, Timmings P, Richens A, Perucca E. Vigabatrin-induced decrease in serum Jienytoin concentiation does not involve a change in phenytoin bioavailability. BrJ Clin Pharmacol (1993) 36,603-6. 

Fig. 15 Effect of phenytoin (PHT) particle size on (a) dissolution in simulated gastric fluid, pH 1.2, 37°C and (b) bioavailability in human volunteers after oral administration of 300 mg PHT. Dark circles lot with particle size range 74-350 /u.m open circles lot with particle size range 177-350 /am. (From Ref. 64.)...

T. Tanino, T. Ogiso, M. Iwaki, G. Tanabe, O. Muraoka, Enhancement of Oral Bioavail-ability of Phenytoin by Esterification, and in vitro Hydrolytic Characteristics of Prodrugs , Int. J. Pharm. 1998, 163, 91 - 102. 

G. K. E. Scriba, D. M. Lambert, Bioavailability of Phenytoin and Anticonvulsant Activity after Oral Administration of Phenytoin-Ws-hydroxyisobutyrate to Rats , Pharm. Res. 1997, 14, 251-253. 

Theophylline is a narrow therapeutic index drug with significant difference in bioavailability following oral administration. The half-life of the drug is increased by heart failure, cirrhosis and viral infections, in elderly patients, and by certain drugs, such as cimetidine, ciprofloxacin, oral contraceptives and fluvoxamine. The half-life is decreased in smokers, chronic alcoholism, and by certain drugs, such as phenytoin, rifampicin and carbamazepine. 

Absorption/Distrlbutlon - Phenytoin is slowly absorbed from the small intestine. Rate and extent of absorption varies and is dependent on the product formulation. Bioavailability may differ among products of different manufacturers. Administration IM results in precipitation of phenytoin at the injection site, resulting in slow and erratic absorption, which may continue for up to 5 days or more. Plasma protein binding is 87% to 93% and is lower in uremic patients and neonates. Volume of distribution averages 0.6 L/kg. Phenytoin s therapeutic plasma concentration is 10 to 20 mcg/mL, although many patients achieve complete seizure control at lower serum concentrations. 

As examples of the range of oral bioavailability a very lipid-soluble drug such as the anticonvulsant phenytoin, or the steroidal anti-inflammatory compound prednisolone, would normally have an oral bioavailability greater than 90%, whereas a very lipid-insoluble drug such as the antibiotic, neomycin, has an oral bioavailability of less than 1%. 

Modified, with permission, from Jusko WJ Bioavailability and disposition kinetics of phenytoin in man. In Kellaway P, Peterson I [editors] Quantitative Analytic Studies in Epilepsy. Raven Press, 1977.)... 

Praziquantel is a synthetic isoquinoline-pyrazine derivative. It is rapidly absorbed, with a bioavailability of about 80% after oral administration. Peak serum concentrations are reached 1-3 hours after a therapeutic dose. Cerebrospinal fluid concentrations of praziquantel reach 14-20% of the drug s plasma concentration. About 80% of the drug is bound to plasma proteins. Most of the drug is rapidly metabolized to inactive mono- and polyhydroxylated products after a first pass in the liver. The half-life is 0.8-1.5 hours. Excretion is mainly via the kidneys (60-80%) and bile (15-35%). Plasma concentrations of praziquantel increase when the drug is taken with a high-carbohydrate meal or with cimetidine bioavailability is markedly reduced with some antiepileptics (phenytoin, carbamazepine) or with corticosteroids. 

Kostenbauder HB, Rapp RP, McGovern JP, et al. Bioavailability and single dose pharmacokinetics of intramuscular phenytoin. Clin Pharmacol Ther 1975 18 449. 

If the therapeutic range of a drug is broad then many substitutions can probably be made. This occurs, for example, with the penicillins. However, if there is a narrow therapeutic range then bioavailability must be carefully considered. Examples of this situation are the use of digoxin (cardiac stimulant) and phenytoin (anticonvulsive). 

Pharmacokinetic studies in dogs demonstrated a 3.5-fold increase in oral bioavailability of phenytoin when administered as the disodium phosphate prodrug versus sodium phenytoin [54]. A few additional examples of investigations with this strategy include the steroids betamethasone [55] and hydrocortisone [56], HIV protease inhibitors [57], and the anticancer drug etoposide [58,59]. Comprehensive reviews of this strategy are also available [52,60,61]. 

Nonlinear relationship of phenytoin dosage and plasma concentrations. Five different patients (identified by different symbols) received increasing dosages of phenytoin by mouth, and the steady-state serum concentration was measured at each dosage. The curves are not linear, since, as the dosage increases, the metabolism is saturable. Note also the marked variation among patients in the serum levels achieved at any dosage. (Modified, with permission, from Jusko WJ Bioavailability and disposition kinetics of phenytoin in man. In Kellaway P, Peterson I [editors]. Quantitative Analytic Studies in Epilepsy. Raven Press, 1977.)... 

S. Chakrabarti and F. M. Belpaire, Bioavailability of phenytoin in lipid containing dosage forms in rats, J. Pharm. Pharmac. 30 330-331 (1978). 

Prodrugs that are more lipophilic than the parent drug can increase membrane pentration and thus oral drag absorption. Thus it was shown that phenytoin 2-monoglyceride, a lipophilic phenytoin prodrug, afforded a 4-fold increase in oral bioavailability in the rat. 

---