Phenytoin clearance

Phenytoin decreases folic add absorption, but folic acid replacement enhances phenytoin clearance and can result in loss of efficacy. Phenytoin tablets and suspension contain phenytoin acid, while the capsules and parenteral solution are phenytoin sodium, which is 92% phenytoin. Clinicians should remember that there are two different strengths of phenytoin suspension and capsules. 

Renal/Hepatic function impairment- Because of an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, interpret total phenytoin plasma concentrations with caution. Unbound phenytoin concentrations may be more useful in these patients. After IV administration, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events. 

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. 

Hayes MJ, Langman MJS, Short AH. Changes in drug metabolism with increasing age 2. Phenytoin clearance and protein binding. BrJ Clin Pharmacol 1975 2 73-79. 

Bachmann K, Schwartz JI, Forney RB Jr, Jauregui L. Single dose phenytoin clearance during erythromycin treatment. Res Commun Chem Pathol Pharmacol 1984 46(2) 207-17. 

Donahue S, Flockhart DA, Abernethy DR. Ticlopidine inhibits phenytoin clearance. Chn Pharmacol Ther 1999 66(6) 563-8. 

Donahue, S., D.A. Flockhart, and D.R. Abemethy (1999). Ticlopidine inhibits phenytoin clearance. Clin. Pharmacol. Ther. 66, 563-568. 

The incidence of phenytoin toxicity may be increased in the eideriy, or in those patients with hepatic or renal impairment, because of alterations in its pharmacokinetics. Plasma level determinations may be indicated in these cases. Although a role for P-glycoprotein transporter alleles in the development of phenytoin toxicity remains controversial, phenytoin is a robust substrate for the non-ABC efflux transporter RLIP76. Because RLIP76 has been found to be overexpressed in excised human epileptic foci, its action may account for treatment failures conversely, inhibition of transport may cause toxicity (34). There is a 2 to 3% increase in the risk of fetal epilepsy syndrome if the mother is taking phenytoin. Phenytoin is contraindicated in cardiac patients with bradyarrhythmias. Induction of CYP2C19 by ginkgo biloba may increase phenytoin clearance and precipitate serious seizures (35). 

Graves, N. M. et al., Phenytoin clearances in a compliant population description and application, Ther. Drug Monit, 8 427-433, 1986. 

B. Extracorporeal removal methods (eg, hemoperfusion and repeat-dose activated charcoal) will enhance phenytoin clearance. Supplemental dosing may be required during such procedures to maintain therapeutic levels. 

Browne TR, Szabo GK, Evans JE, Evans BA, GreenblattDJ, Mkati MA Carbamazepine increases phenytoin serum concentration and reduces phenytoin clearance. Neurology (1988) 38,1146-50. 

Gratz ES, Theodore WH, Newmark ME, Kupferberg HJ, Porter RJ, Qu Z. Effect of carbamazepine on phenytoin clearance in patients with complex partial seizures. Neurology (1982)32,A223. 

Frigo GM, Lecchini S, Caravaggi M, Gatti G, Tonini M, D Angelo L, Perucca E, Crema A. Reduction of phenytoin clearance caused by cimetidine. EurJ Clin Pharmacol (1983) 25, 135-7. 

A single-dose study found that the mean clearance of phenytoin was unchanged by erythromycin 333 mg every 8 hours for 7 days in 8 healthy subjects. However, there were occasional large changes in phenytoin clearance. Similarly, in another study erythromycin 250 mg every 6 hours for 7 days had no effect on the pharmacokinetics of a single dose of phenytoin in 8 healthy subjects. ... 

In the first study above, 3 of the 12 patients had a decrease in phenytoin clearance and an increase of 25 to 55% in the AUC of phenytoin when taking topiramate the other 9 had no changes. This slight increase is said not to be clinically significant based on analyses from six add-on studies. ... 

Equation to adjust measured phenytoin levels in the setting of creatinine clearance <10 mL/min +/- hypoalbuminemia... 

Cholestyramine, calcium carbonate, sucralfate, aluminum hydroxide, ferrous sulfate, soybean formula, and dietary fiber supplements may impair the absorption of levothyroxine from the GI tract. Drugs that increase nondeiodinative T4 clearance include rifampin, carbamazepine, and possibly phenytoin. Amiodarone may block the conversion of T4 to T3. 

Factors that may enhance theophylline clearance and result in the need for higher doses include tobacco and marijuana smoking, hyperthyroidism, and use of drugs such as phenytoin, phenobarbital, and rifampin. 

When a preparation of phenytoin was administered to a patient, the volume of distribution was found to be 70 liters, and the half-life of elimination was 1.5 hours. What is the total clearance of phenytoin ... 

The clearance of a drug is usually defined as the rate of elimination of a compound in the urine relative to its concentration in the blood. In practice, the clearance value of a drug is usually determined for the kidney, liver, blood or any other tissue, and the total systemic clearance calculated from the sum of the clearance values for the individual tissues. For most drugs clearance is constant over the therapeutic range, so that the rate of drug elimination is directly proportional to the blood concentration. Some drugs, for example phenytoin, exhibit saturable or dose-dependent elimination so that the clearance will not be directly related to the plasma concentration in all cases. 

The consideration of clearance in units of volume per maximum life span potential, instead of the traditional volume per weight, provides an allometric relationship for drugs such as antipyrine and phenytoin [17]. Both of these dmgs are essentially low clearance compounds, cleared by P450 metabolism. Ultimately, the successful utility of such factors may be purely serendipitous as they simply exploit unique features of man as a species. 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

The apparent clearance of lamotrigine is affected by the coadministration of AEDs. Lamotrigine is eliminated more rapidly in patients who have been taking hepatic enzyme inducing antiepileptic drugs (ElAEDs), including carbamazepine, phenytoin, phenobarbital, and primidone. 

Deravirdine (Rescnptor) [Antiretroviral/NNRTI] Uses HIV Infxn Action Nonnucleoside RT inhibitor Dose 400 mg PO tid Caution [C, ] CDC recommends HIV-infected mothers not to breast-feed (transmission risk) w/ renal/hepatic impair Contra Use w/ drugs dependent on CYP3A for clearance (Table VI-8) Disp Tabs SE Fat redistribution, immune reconstitution synd, HA, fatigue, rash, T transaminases, N/V/D Interactions T Effects W/ fluoxetine T effects OF benzodiazepines, cisapride, clarithromycin, dapsone, ergotamine, indinavir, lovastatin, midazolam, nifedipine, quinidine, ritonavir, simvastatin, terfena-dine, triazolam, warfarin effects W/ antacids, barbiturates, carbamazepine, cimetidine, famotidine, lansoprazole, nizatidine, phenobarbital, phenytoin, ranitidine, rifabutin, rifampin effects OF didanosine EMS Use of benzodiazepines and CCBs should be avoided may cause a widespread rash located on upper body and arms OD May cause an extension of nl SEs symptomatic and supportive Deferasirox (Exjade) [Iron Chelator] Uses Chronic iron overload d/t transfusion in pts >2 y Action Oral iron chelator Dose Initial 20 mg/kg... 

However, for some drugs, such as the anticonvulsant phenytoin, there is good evidence that Vd is not altered and that oxidative clearance is greater than in adult patients. 

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

The concurrent administration of lidocaine with cimeti-dine but not ranitidine may cause an increase (15%) in the plasma concentration of lidocaine. This effect is a manifestation of cimetidine reducing the clearance and volume of distribution of lidocaine. The myocardial depressant effect of lidocaine is enhanced by phenytoin administration. 

All quinolones interact with multivalent cations, forming chelation complexes resulting in reduced absorption. Major offenders are antacids vitamins containing calcium and iron can also be problematic. All fluoroquinolones interact with warfarin, didanosine (ddi), and phenytoin, resulting in decreased absorption or metabolism. Ciprofloxacin and other second-generation drugs interact with theophylline by decreasing its clearance, which leads to theophylline toxicity. 

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