Pharmacokinetics phenytoin

TR Browne, JE Evans, GK Szabo, BA Evans, DJ Greenblatt, GE Schumacher. Studies with stable isotopes. I. changes in phenytoin pharmacokinetics and biotransformation during monotherapy. J Clin Pharmacol 25 43—50, 1985. 

Shavit G, Lerman P, Konczyn AD et al (1984) Phenytoin pharmacokinetics in catamenial epilepsy. Neurology 34 959-61. 

Olanow CW, Finn A, Prussak C. The effect of salicylate on phenytoin pharmacokinetics. Trans Am Neurol Assoc ( 919) 104, 109-10. 

T ownsend RJ, Fraser DG, Scavone JM, Cox SR The effects of ibuprofen on phenytoin pharmacokinetics. Drug InUll Clin Pharm (1985) 19,447-8. 

In a study in healthy subjects the concurrent use of posaconazole 200 mg daily and phenytoin 200 mg daily for 10 days decreased the AUC of posaconazole by 50%, when compared to controls. Although there was no statistically significant change in phenytoin pharmacokinetics, some subjects had increases in phenytoin levels that could be clinically relevant. ... 

Purkins L, Wood N, Ghahramani P, Love E Eve MD, F ielding A. Coadministration of voriconazole and phenytoin pharmacokinetic interaction, safety, andtoleraticm. BrJ Clin Pharmacol 2003) 56, 37-44. 

Established interactions. The phenytoin dosage may need to be reduced (a 20 to 40% reduction seems to be about right / ) if felbamate is added, and to increase it if felbamate is withdrawn. However, note that as phenytoin pharmacokinetics are non-linear any dosage adjustments will need to be assessed in individual patients. The importance of the reduced felbamate levels is uncertain, but is probably less important because felbamate has a wide therapeutic range. ... 

One study found that the half-life of phenytoin was modestly prolonged by metronidazole, whereas another found no change in phenytoin pharmacokinetics. An anecdotal report describes a few patients who developed toxic phenytoin levels when given metronidazole. 

Karol MD, Mukherji D, Cavanaugh JH. Lack of effect of concomitant multi-dose lansoprazole on single-dose phenytoin pharmacokinetics in subjects, Gastroenterology (1994) 106, A103. 

PrichardPJ, WaltRP,Kitchin an GK, SomervilleKW,LangmanMJS, Williams J, Richens A. Oral phenytoin pharmacokinetics during omeprazole therapy. BrJ Clin Pharmacol (1987) 24, 543-5. 

A group of 10 patients taking phenytoin were also given up to 300 mg remaeemide twice daily for 2 weeks. On average remaeemide did not affect phenytoin pharmacokinetics but 5 patients had an increase in mini-... 

The preliminary report of a study notes that the clearance of retigabine was increased (amount not stated) by carbamazepine and phenytoin, whereas retigabine did not alter carbamazepine or phenytoin pharmacokinetics in patients with epilepsy. This is consistent with the known enzyme-inducing properties of carbamazepine and phenytoin, and the fact that retigabine has not been shown to induce hepatic enzymes. In contrast, in a study in healthy subjects, phenobarbital 90 mg daily did not affect the pharmacokinetics of retigabine 200 mg every 8 hours, and the pharmacokinetics... 

Sachdeo RC, Sachdeo SK, Levy RH, Streeter AJ, Bishop FE, Kimze KL, Mather GG, Roskos LK, Shen DD, Thummel KE, Trager WF, Curtin CR, Doose DR, Gisclon LG, Dialer M. Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients. Epilepsia (2002) 43 691. ... 

Patrias JM, DiPiro JT, Cheung RPF, Townsend RJ. Effect of alprazolam on phenytoin pharmacokinetics, Drug Intell Clin Pharm (1987) 21,2A. 

The antiepileptic drug phenytoin, an orally available class DB antiarrhythmic, is mainly effective in digitalis-induced arrhythmias. This diug exhibits nonlinear pharmacokinetics and a number of side effects including neuropathy, gingival hypetplasia, hepatitis, immunological disorders and suppression of white blood cells. 

Neovonen PJ. BioavailabUity of phenytoin dinical pharmacokinetic and therapeutic implications. Clin Pharmacokinet 1979 22 247-53. 

Elderly- Age does not have a significant impact on the pharmacokinetics of fosphenytoin following administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required. 

Mamiya K, leiri I, Shimamoto J, Yukawa E, Imai J, Ni-nomiya H et al. The effects of genetic polymorphims of CYP2C9 and CYP2C19 on phenytoin metabohsm in Japanese adult patients with epilepsy studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 1998 29(12) 1317-23. 

Theoretical depiction of phenytoin concentrations achieved following various doses of the antiepileptic phenytoin. Shaded area indicates the therapeutic range of phenytoin concentrations below 10 (xg/mL, results in subtherapeutic effect above 20 (xg/mL, results in toxicity. Within the therapeutic range, a relatively small increase in dose results in a greater than proportional increase in concentration, suggesting nonlinear pharmacokinetics. 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Two patients stabilized on a phenytoin regimen suffered a loss of seizure control after taking shankhapushpi, an Ayurvedic antiepileptic medicine, three times a day. There was also a significant decrease in serum phenytoin concentration from 9.6 to 5.1mg/L. To investigate the possible mechanisms, multiple doses of shankhapushpi were administered to rats and resulted in decreased plasma phenytoin concentrations, whereas single-dose administration was reported to interfere with the antiplatelet effect of phenytoin, thereby implying both a pharmacokinetic and pharmacodynamic basis for the interaction (73). 

Non-linear pharmacokinetics are much less common than linear kinetics. They occur when drug concentrations are sufficiently high to saturate the ability of the liver enzymes to metabolise the drug. This occurs with ethanol, therapeutic concentrations of phenytoin and salicylates, or when high doses of barbiturates are used for cerebral protection. The kinetics of conventional doses of thiopentone are linear. With non-linear pharmacokinetics, the amount of drug eliminated per unit time is constant rather than a constant fraction of the amount in the body, as is the case for the linear situation. Non-linear kinetics are also referred to as zero order or saturation kinetics. The rate of drug decline is governed by the Michaelis-Menton equation ... 

The antiseizure drugs exhibit many similar pharmacokinetic properties—even those whose structural and chemical properties are quite diverse— because most have been selected for oral activity and all must enter the central nervous system. Although many of these compounds are only slightly soluble, absorption is usually good, with 80-100% of the dose reaching the circulation. Most antiseizure drugs (other than phenytoin and valproic acid) are not highly bound to plasma proteins. 

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

Wood, R. W., Clemente, W., Lambert, McShane, J. (190ffi)gle Dose Pharmacokinetic Comparison of Oral Phenytoin Administered as a Novel Nanocrystal Dispei dE( lantin-125 Suspension or Dilantin Kapseals, 24th Annual Meeting ACCP... 

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]. 

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