Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine.

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Giancarlo GM, Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ

Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine.

Eur J Clin Pharmacol. 2001 Apr;57(1):31-6.

PubMed ID

11372587 [ View in PubMed

]

Abstract

OBJECTIVES: To determine the relative contribution of cytochromes P450 (CYP) 2C9 and 2C19 to the formation of 5-(-4-hydroxyphenyl)-5-phenylhydantion (HPPH) from phenytoin (PPH). DESIGN: Hydroxylation of PPH to form HPPH was studied in vitro using human liver microsomes and microsomes from cDNA-transfected human lymphoblastoid cells. RESULTS: Formation of HPPH from PPH in liver microsomes had a mean (+/- SEM) apparent Km [substrate concentration corresponding to 50% of maximal reaction velocity (Vmax)] of 23.6 +/- 1.8 mumol/l. Coincubation with the CYP2C9 inhibitor, sulfaphenazole (SPA), at 5 mumol/l reduced reaction velocity to less than 15% of control values. The mean inhibitor concentration at which 50% inhibition is achieved (IC50 value) for SPA versus PPH hydroxylation (0.49 microM) was similar to the SPA IC50 versus flurbiprofen hydroxylation (0.46 microM) and tolbutamide hydroxylation (0.7-1.5 microM). In contrast, the CYP2C19 inhibitor omeprazole (OME) at 10 mumol/l produced only a small degree of inhibition. Incubation of PPH with microsomes from cDNA-transfected human lymphoblastoid cells containing CYP1A2, 2A6, 2B6, 2C8, 2D6, 2E1, or 3A4 yielded no detectable formation of HPPH. Only CYP2C9 and 2C19 had PPH hydroxylation activity, with apparent Km values for the high-affinity component of 14.6 mumol/l and 24.1 mumol/l, respectively. Based on Vmax values in liver microsomes, the Vmax and Km values in expressed CYPs and the relative abundance of the two isoforms in human liver, CYP2C9, and 2C19 were estimated to have relative contributions of 90% and 10%, respectively, to net intrinsic clearance. CONCLUSIONS: Formation of HPPH from PPH is mediated exclusively by CYP2C9 and 2C19, with CYP2C9 playing the major role.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Phenytoin	Cytochrome P450 2C19	Protein	Humans	No	Substrate Inducer	Details
Ticlopidine	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate Inhibitor	Details
Ticlopidine	Cytochrome P450 2C9	Protein	Humans	Unknown	Inhibitor	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
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Fosphenytoin Felbamate	The serum concentration of Fosphenytoin can be increased when it is combined with Felbamate.
Fosphenytoin Sulfaphenazole	The serum concentration of Fosphenytoin can be increased when it is combined with Sulfaphenazole.
Phenytoin Felbamate	The serum concentration of Phenytoin can be increased when it is combined with Felbamate.
Phenytoin Sulfaphenazole	The serum concentration of Phenytoin can be increased when it is combined with Sulfaphenazole.