Phenytoin, polymorphic

While generally not of major concern, omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin lansoprazole may decrease theophylline concentrations. Drug interactions with omeprazole are of particular concern in patients who are considered slow metabolizers, as are approximately 3% of the Caucasian population. Unfortunately, it is unclear which patients have the polymorphic gene variation that makes them slow metabolizers.17 The metabolism of esomeprazole may also be altered in patients with this polymorphic gene variation. Patients on potentially interacting drugs should be monitored for development of drug-related problems. 

Qi, X. 1., Huang, Y., Wang, Y. Q. et al. (2004). Association of plasma sodium phenytoin concentration with CYP2C19 gene polymorphism. Chinese Journal of New Drugs, 13( 10), 922-5. 

Ibeanu GC, Blaisdell ], Ferguson R], Ghanayem Bl, Brosen K, Benhamou S et al. A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-me-phenytoin. J Pharmacol Exp Ther 1999 290[2] 635—640. 

Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang TY, Liao XM et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquine and S-me-phenytoin. Clin Pharmacol Ther 1992 51 388-397. 

CYP2C9 Phenytoin, warfarin, nonsteroidal antiinflammatory drugs Polymorphic... 

Figure 4 Polymorphic drug oxidations by cytochrome P450. A, substrates subject to debrisoquine/sparteine polymorphism. R(+)-bufuralol is I -hydroxyl-ated by P450-IID6 the S(—)-enantiomer undergoes hydroxylation at the 2- and 4-positions debrisoquine is hydroxylated at the prochiral C4-atom to S(+)-hydroxy-debrisoquine sparteine metabolism by P450-IID6 consists of N-oxidation. B, substrates subject to hydantoin polymorphism (4 -hydroxylation). Extensive metabolizers convert S(+)-mephenytoin and -nirvanol to the 4 -hydroxy derivative (indicated by the arrow). Similarly, EMs metabolize the prochiral drug phenytoin to R(+)-4 -hydroxyphenytoin. = chiral center.

Ninomiya H, Mamiya K, Matsuo S, leiri I, Higuchi S, Tashiro N. Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin concentration with central nervous system intoxication. Ther Drug Monit 2000 22(2) 230-2. 

Kerb R, Aynacioglu AS, Brockmoller J, Schlagenhaufer R, Bauer S, Szekeres T, et al. The predictive value of MDRl, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels. Pharmacogenomics J 2001 1 204-10. 

Mamiya K, leiri I, Shimamoto J, Yukawa E, Imai J, Ninomiya H, et al. The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy studies m stereoselective hydroxylation and population pharmacokinetics. Epilepsia 1998 39 1317-23. 

A. Odani, Y. Hashimoto, Y. Otsuki, Y. Uwai, H. Hattori, K. Furusho, and K. Inui, Genetic polymorphisms of the CYP2C sub-family and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy. Clin Pharmacol Ther 62 287-292. 

The majority of the crystallization literature deals with inorganic crystals, and the organic chemistry literature mainly covers small organic molecules with few degrees of freedom such as glutamic acid, phenytoin, or paracetamol. The reality in the pharmaceutical industry is often much more complicated— molecular weights above 1000 g/mole are common, and complex molecular structures have an effect on nucleation and growth kinetics as well as on the likelihood of polymorph formation. 

Chaudhry AS, Urban TJ, Lamba JK, Bimbaum AK, Remmel RP, Subramanian M, Strom S, You JH, Kasperaviciute D, Catarino CB, Radtke RA, Sisodiya SM, Goldstein DB, Schuetz EG (2010) CYP2C9 1B promoter polymorphisms, in linkage with CYP2C19 2, affect phenytoin autoinduction of clearance and maintenance dose. J Pharmacol Exp Ther 332 599-611... 

---