Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects.

The aim of this study was to investigate which principal human cytochrome P450 (CYP450) enzymes are affected by artemisinin and to what degree the artemisinin derivatives differ with respect to their respective induction and inhibition capacity. Seventy-five healthy adults were randomized to receive therapeutic oral doses of artemisinin, dihydroartemisinin, arteether, artemether or artesunate for 5 days (days 1-5). A six-drug cocktail consisting of caffeine, coumarin, mephenytoin, metoprolol, chlorzoxazone and midazolam was administered orally on days -6, 1, 5 and 10 to assess the activities of CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Four-hour plasma concentrations of parent drugs and corresponding metabolites and 7-hydroxycoumarin urine concentrations were quantified by liquid chromatography-tandem mass spectrometry. The 1-hydroxymidazolam/midazolam 4-h plasma concentration ratio (CYP3A) was increased on day 5 by artemisinin [2.66-fold (98.75% CI: 2.10-3.36)], artemether [1.54 (1.14-2.09)] and dihydroartemisinin [1.25 (1.06-1.47)] compared with day -6. The S-4'-hydroxymephenytoin/S-mephenytoin ratio (CYP2C19) was increased on day 5 by artemisinin [1.69 (1.47-1.94)] and arteether [1.33 (1.15-1.55)] compared with day -6. The paraxanthine/caffeine ratio (CYP1A2) was decreased on day 1 after administration of artemisinin [0.27 (0.18-0.39)], arteether [0.70 (0.55-0.89)] and dihydroartemisinin [0.73 (0.59-0.90)] compared with day -6. The alpha-hydroxymetoprolol/metoprolol ratio (CYP2D6) was lower on day 1 compared with day -6 in the artemisinin [0.82 (0.70-0.96)] and dihydroartemisinin [0.83 (0.71-0.96)] groups, respectively. In the artemisinin-treated subjects this decrease was followed by a 1.34-fold (1.14-1.58) increase from day 1 to day 5. These results show that intake of artemisinin antimalarials affect the activities of several principal human drug metabolizing CYP450 enzymes. Even though not significant in all treatment groups, changes in the individual metrics were of the same direction for all the artemisinin drugs, suggesting a class effect that needs to be considered in the development of new artemisinin derivatives and combination treatments of malaria.

Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital.

The simultaneous dosing of two drugs with co-regulated genetic polymorphisms determined by a single cytochrome P-450 isozyme could result in competitive inhibition of metabolism. We investigated this hypothesis in vivo by studying the interaction of mephobarbital and mephenytoin in eight normal subjects with wide variability in S-mephenytoin 4-hydroxylation. Each received oral racemic mephenytoin (100 mg) alone and, on a separate occasion, 1 hour after oral racemic mephobarbital (200 mg). After mephenytoin dosing alone, the 8-hour urinary enantiomeric (R/S) ratio indicated one poor (PM), one intermediate (IM), and six extensive (EM) metabolizers. Total intrinsic clearance of S-mephenytoin varied more than 100-fold, whereas the range for R-mephenytoin was only twofold. The urinary R/S ratio correlated (r = 0.92) with the enantiomeric ratio of the plasma AUCs over the same period, indicating no stereoselectivity in renal clearance. When mephenytoin was taken in the presence of mephobarbital, peak levels and AUC of S-mephenytoin increased while those of the R-enantiomer remained unchanged. Accordingly, the R/S ratios in both plasma and urine were reduced, with the change rank order-related to the control value of the total intrinsic clearance of S-mephenytoin (i.e., greatest in the most extensive EM). Thus the urinary R/S ratio can be used as a measure of the enantiomeric ratio of the plasma concentrations over the same time period of collection. Moreover, this ratio may be used to detect drug interactions that involve the cytochrome P-450 isozyme(s) responsible for the polymorphic 4-hydroxylation of mephenytoin.(ABSTRACT TRUNCATED AT 250 WORDS)

Mephenytoin disposition and serum bile acids as indices of hepatic function in chronic viral hepatitis.

BACKGROUND AND OBJECTIVES: The effect of chronic viral hepatitis on liver function may vary from none to hepatic failure. Changes in function are usually the result of impaired hepatocyte function or altered vascular flow and architecture. Conventional liver function tests usually cannot distinguish contributions from these mechanisms or indicate degree of hepatic metabolic dysfunction. An alternative approach is to measure the hepatic metabolism of a highly extracted compound whose oral clearance and systemic bioavailability are dependent on both hepatocyte function and degree of portosystemic shunt. METHODS: The stereoselective metabolism of racemic mephenytoin (100 mg oral dose) was investigated in 35 patients with chronic viral hepatitis and compared with 153 healthy subjects. The mephenytoin R/S enantiomeric ratio and cumulative excretion of the 4'-hydroxymephenytoin metabolite in a 0- to 8-hour urine sample were used in addition to serum bile acid levels and pathologic examination of biopsy specimens to assess the severity of hepatic dysfunction and portosystemic shunting. RESULTS: The patients as a group excreted less 4'-hydroxymephenytoin and had a smaller R/S enantiomeric ratio of mephenytoin. The two measures were discriminatory between the patient groups classified by either serum cholylglycine level or pathologic examination of biopsy specimens. Combination of the two measures of mephenytoin metabolism allowed the patients to be classified into three groups: normal hepatocyte function without portosystemic shunt, normal hepatocyte function with portosystemic shunt, and low hepatocyte function with or without portosystemic shunt. CONCLUSION: This study has shown the potential usefulness of mephenytoin metabolism as a sensitive indicator of hepatic pathologic condition with an ability to discriminate between contributory alternative mechanisms.

Dapsone N-acetylation, metoprolol alpha-hydroxylation, and S-mephenytoin 4-hydroxylation polymorphisms in an Indonesian population: a cocktail and extended phenotyping assessment trial.

We examined dapsone N-acetylation and metoprolol alpha-hydroxylation and S-mephenytoin 4-hydroxylation phenotypings using the respective test probes (dapsone and racemic metoprolol and mephenytoin) administered separately and in a cocktail manner to an Indonesian subject group (n = 30). After ascertaining that the separate and cocktail phenotyping tests of the probe drugs correlated with each other (all rs values > 0.84; p < 0.001), the cocktail phenotyping assessment was extended to the other 74 Indonesians. In a total of 104 Indonesians phenotyped with the cocktail test, a visual antimode was apparent only in the dapsone N-acetylation and S-mephenytoin 4-hydroxylation polymorphisms: the frequencies of slow acetylators and poor hydroxylators were 43.3% (95% confidence interval, 33.7% to 52.8%) and 15.4% (95% confidence interval, 8.5% to 22.3%), respectively. The distribution histogram and probit plots of the metabolic ratio of metoprolol gave no clear evidence for bimodality, and therefore no poor alpha-hydroxylator of metoprolol was considered to exist in the present sample size. The findings indicate that the Indonesian subjects have a greater incidence of slow acetylator phenotype compared with Japanese and Chinese, as well as a frequency of poor metabolizer phenotype of S-mephenytoin similar to that of Korean and Chinese subjects. They resemble an African population (Nigerians) in metoprolol alpha-hydroxylation polymorphism, with no apparent antimode derived from white populations.

No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects.

BACKGROUND: Although it is known that the use of oral contraceptives inhibits oxidative drug metabolism, there is little information regarding their effect on CYP2C19 activity. Moreover, earlier reports suggest that there may be differences in CYP2C19 activity between men and women. OBJECTIVE: We sought to assess the effect of sex and intake of oral contraceptives on CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole. METHODS: To determine CYP2C19 activity in white Swedish subjects, 644 subjects previously phenotyped with mephenytoin and 175 subjects phenotyped with omeprazole were investigated. The 8-hour urinary mephenytoin S/R ratio after ingestion of 100 mg mephenytoin and the plasma concentration ratio of omeprazole/hydroxyomeprazole at 3 hours after ingestion of 20 mg omeprazole were used as measures of CYP2C19 activity. Differences in these ratios and in their frequency distributions were then examined among women with and without oral contraceptives and men. In addition, nearly all subjects in the omeprazole group had been genotyped with regard to the CYP2C19*2 (ml) allele. Subjects homozygous for the CYP2C19*2 allele were excluded from the study. RESULTS: The median mephenytoin S/R ratio was 2.5-fold higher in the subgroup of women taking oral contraceptives compared with either women not taking oral contraceptives (P < .001) or men (P < .001). Similarly, the mean omeprazole/hydroxyomeprazole ratio was twice as high in the oral contraceptive group compared with women not taking oral contraceptives (P < .001) or men (P < .001). However, no differences were evident between women not taking oral contraceptives and men in either the mephenytoin group (P = .48) or the omeprazole group (P = .77). The oral contraceptive-induced inhibitory effect on CYP2C19 activity was similar between the CYP2C19*1/*1 and *1/*2 genotypes, and they were independent of age. CONCLUSIONS: Intake of oral contraceptives significantly inhibits CYP2C19 activity, but there is no true sex-related difference in CYP2C19 activity in healthy, white, Swedish subjects.

Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6.

BACKGROUND AND OBJECTIVES: Drug metabolism is influenced by liver disease because of the central role that the liver plays in metabolic activities in the body. However, it is still unclear how activities of specific drug-metabolizing enzymes are influenced by the presence and severity of liver disease. As a consequence, alteration in metabolism of specific drugs cannot be easily predicted or appropriate dosage adjustment recommendations made. METHODS: The activities of cytochromes P450 (CYP) 2C19 and 2D6 were investigated in a group of patients with mild or moderate liver disease (n = 18) and a group of healthy control subjects (n = 10). The disposition of racemic mephenytoin for CYP2C19 and debrisoquin for CYP2D6 were characterized in plasma and urine samples collected over 192 hours. RESULTS: The elimination of S-mephenytoin was severely reduced among patients with liver disease, resulting in a 79% decrease in plasma clearance for all patients combined. This reduction was related to the severity of disease, patients with moderate disease being affected more severely than patients with mild disease. Similar differences were observed in the urinary excretion of 4'-hydroxymephenytoin metabolite. By contrast, there was no effect on the disposition of R-mephenytoin or debrisoquin. CONCLUSION: These results show selectivity in the effect of liver disease on activities of specific metabolizing enzymes, CYP2C19 being more sensitive than CYP2D6. They suggest that recommendations for modification in drug dosage in the presence of liver disease should be based on knowledge of the particular enzyme involved in metabolism of the drug. The results emphasize the need for further studies of each specific drug-metabolizing enzyme in the presence of liver disease.

Disposition of mephenytoin and its metabolite, nirvanol, in epileptic patients.

We investigated the conversion of mephenytoin to nirvanol in five patients with uncontrolled complex partial seizures. After a 50-mg single oral dose, mean peak mephenytoin level was 0.48 microgram/ml and nirvanol 0.37 microgram/ml. After 400 mg, peak mephenytoin level was 3.9 micrograms/ml and nirvanol 2.5 micrograms/ml. On 400 mg daily, mephenytoin reached a mean steady-state level of 1.5 micrograms/ml. Nirvanol mean steady-state level was 18 micrograms/ml. Mean plasma half-life was 17 hours for mephenytoin and 114 hours for nirvanol. Two patients had reduced seizures during mephenytoin therapy and one a transient increase during drug withdrawal. No toxicity was seen, but mephenytoin was not more effective than phenytoin.

Interaction of serum proteins with CYP isoforms in human liver microsomes: inhibitory effects of human and bovine albumin, alpha-globulins, alpha-1-acid glycoproteins and gamma-globulins on CYP2C19 and CYP2D6.

The effects of serum proteins on the in vitro hydroxylation pathways of mephenytoin (CYP2C19) and debrisoquine (CYP2D6) were studied to enhance the predictability of in vivo drug metabolism from in vitro assays. Both CYP substrates are known to be weakly bound to albumin and the applicability of the free drug hypothesis was further appraised. Since bovine serum albumin (BSA) is used widely in in vitro assays, a comparison between human and bovine proteins was made. Four major serum proteins were studied: albumin, alpha1-acid glycoprotein (AGP), alpha- and gamma-globulins. Human serum albumin (HSA) inhibited both CYP activities about 20% more than BSA. The addition of human alpha-globulins, but not the bovine protein, resulted in marked reduction of 86% and 41% in CYP2C19 and CYP2D6 activities, respectively. This reduction of activity was strikingly greater than the fraction bound (14 and 22%, respectively). The inhibition was of the competitive type and the Ki values of human alpha-globulins on CYP2C19 and CYP2D6 were found to be 0.45% (4.5 mg/ml) and 3.5% (35 mg/ml), respectively. The effect of both human and bovine gamma-globulins on CYP isoforms was negligible. The Ki values of human and bovine AGP for CYP2C19 were 1.84% (420 microM) and 0.93% (210 microM), respectively. For HSA, human alpha-globulins and human and bovine AGP, the strongly decreased CYP activities in vitro cannot be explained by the free drug hypothesis. A direct interaction of these serum proteins with CYP enzymes is postulated. Differential effects of bovine and human serum proteins and CYP specific inhibition were observed.

Simultaneous enantiospecific separation and quantitation of mephenytoin and its metabolites nirvanol and 4'-hydroxymephenytoin in human plasma by liquid chromatography.

A high-performance liquid chromatographic method for the enantiospecific quantitation of S- and R-mephenytoin and its metabolites S- and R-nirvanol and S- and R-4'-hydroxymephenytoin in plasma is described. The compounds were separated using a reversed-phase C(2) column in tandem with a chiral alpha(1)-acid glycoprotein column and were detected using ultraviolet detection at 205 nm. The lower limit of quantification was 10 ng/ml for all compounds using 0.5 ml human plasma (intra-day coefficient of variation <13%, accuracy <+/-20%). The method was validated for human plasma in the concentration range 10-2000 ng/ml for each of the six compounds. The method allows for the simultaneous characterisation of the metabolic capacity of two human drug-metabolising enzymes, CYP2C19 and CYP2B6, and may be used when investigating polymorphisms or changes in activity of these two enzymes.

Mephenytoin stereoselective elimination in the rat: III. Stereoselective time course of induction during chronic hepatic portal vein administration.

The blood concentrations of R- and S-mephenytoin were followed in seven rats over a 5-8 day period during a hepatic portal vein infusion of racemic mephenytoin. In all but two rats, both of the enantiomers achieved an initial steady-state level before a measurable change was observed in their blood concentrations. In each case, the decrease in the initial S-mephenytoin steady state blood level occurred after the change in R-mephenytoin was apparent. During the period of study, the mean +/- SD portal vein clearance of S-mephenytoin increased from 96 +/- 33 ml/h to 450 +/- 160 ml/h. The mean +/- SD portal vein clearance of R-mephenytoin increased from 170 +/- 50 ml/h to 2400 +/- 1600 ml/h. The larger increase in the portal vein clearance for the R-enantiomer resulted in the R/S-mephenytoin clearance ratio over this same time period changing from 1.8 +/- 0.2 to 5.2 +/- 1.8. Attempts to describe the time course of change in the clearance of S- or R-mephenytoin using a previously reported model of induction were unsuccessful. The induction time course did suggest, however, that the rate of induction may be similar for each enantiomer.

[Determination of phenobarbital, mephenytoin and diphenylhydantoin in the surveillance of anticonvulsant treatment]. / Dosage du phénobarbital, de la méphénytoïne et de la diphénylhydantoïne dans la surveillance du traitement des anticonvulsivants

The authors describe a method of simultaneous estimation of phenobarbitone, mephenytoin and diphenylhydantoin in the blood. After extraction with ether, the methylation of these substances by trimethylanilinium hydroxide permits their rapid separation by gas chromatography. Heptabarbitone is used as internal standard and the chromatograph used is supplied with a thermoionic detector. The technique used is simple and rapid. Its reproducibility and sensitivity are satisfactory, permitting daily application to the supervision of anticonvulsant treatment, especially in Pediatrics.

Enantiospecific separation and quantitation of mephenytoin and its metabolites nirvanol and 4'-hydroxymephenytoin in human plasma and urine by liquid chromatography/tandem mass spectrometry.

A sensitive method using enantiospecific liquid chromatography/tandem mass spectrometry detection for the quantitation of S- and R-mephenytoin as well as its metabolites S- and R-nirvanol and S- and R-4'-hydroxymephenytoin in plasma and urine has been developed and validated. Plasma samples were prepared by protein precipitation with acetonitrile, while urine samples were diluted twice with the mobile phase before injection. The analytes were then separated on a chiral alpha(1)-acid glycoprotein (AGP) column and thereafter detected, using electrospray ionization tandem mass spectrometry. In plasma, the lower limit of quantification (LLOQ) was 1 ng/mL for S- and R-4'-hydroxymephenytoin and S-nirvanol and 3 ng/mL for R-nirvanol and S- and R-mephenytoin. In urine, the LLOQ was 3 ng/mL for all compounds. Resulting plasma and urine intra-day precision values (CV) were <12.4% and <6.4%, respectively, while plasma and urine accuracy values were 87.2-108.3% and 98.9-104.8% of the nominal values, respectively. The method was validated for plasma in the concentration ranges 1-500 ng/mL for S- and R-4'-hydroxymephenytoin, 1-1000 ng/mL for S-nirvanol, and 3-1500 ng/mL for R-nirvanol and S- and R-mephenytoin. The validated concentration range in urine was 3-5000 ng/mL for all compounds. By using this method, the metabolic activities of two human drug-metabolizing enzymes, cytochrome P450 (CYP) 2C19 and CYP2B6, were simultaneously characterized.

Gas-chromatographic determination of mephenytoin and desmethylmephenytoin, after off-column alkylation.

We describe a gas-liquid chromatographic method for determining mephenytoin and its active metabolite, desmethylmephenytoin, in human serum. 5-Methyl-5-phenylhydantoin is used as the internal standard. The method involves extraction of the drugs by adsorption onto charcoal and off-column derivatization to their pentyl derivatives. Peak height and concentration are linearly related and the day-to-day CV for therapeutic concentration is about 2 to 6%. No interferences by endogenous compounds or drugs commonly used for seizure control have been encountered.

Direct enantiomeric resolution of mephenytoin and its N-demethylated metabolite in plasma and blood using chiral capillary gas chromatography.

A gas chromatographic method was developed for the determination of the R- and S- enantiomers of the anticonvulsant, mephenytoin, and its N-demethylated metabolite, 5-phenyl-5- ethylhydantoin ( PEH ), in plasma and blood. Direct enantiomeric separation of mephenytoin and its internal standard was obtained using a chiral capillary column ( Chirasil -Val) followed by nitrogen specific detection. However, resolution of the enantiomers of PEH and its internal standard required propylation at the 3-position of the hydantoin ring prior to analysis. Similar linear and reproducible standard curves were obtained from both plasma and blood over the concentration range 50 ng/ml to 5 micrograms/ml, and above 100 ng/ml the reproducibility was less than 8% (coefficient of variation). Pronounced stereoselective differences in the plasma concentration--time curves for both mephenytoin and PEH were observed in a normal subject who received a single oral dose of 300 mg racemic mephenytoin. The peak plasma level of S-mephenytoin was only one-fifth that of the R-enantiomer and its elimination half-life was less than 3 h compared to over 70 h for R-mephenytoin. Similarly, S- PEH levels were barely detectable whereas concentrations of R-metabolite steadily increased over 4-6 days before slowly declining.

Measurement of mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) and its demethylated metabolite by selective ion monitoring.

Mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) and its demethylated metabolite Nirvanol (5-ethyl-5-phenylhydantoin) were measured by a selective ion monitoring technique. This method was used in the analysis of both compounds in plasma from a patient receiving 50 mg and 400 mg of mephenytoin in single oral doses. Both compounds were extracted from plasma and ethylated prior to analysis by electron-impact mass spectrometry. Alkylation, using ethyl iodide in 2-butanone, occurred in the N-1 and N-3 positions of the hydantoin ring when concentrated KOH was added to the reaction mixture. The lower limits of quantitation for mephenytoin and Nirvanol were 10 ng/ml and 50 ng/ml, respectively, and were found to be reproducible within 8% upon repeated quantification.

Increased systemic availability of drugs during acute ethanol intoxication: studies with mephenytoin in the dog.

The influence of ethanol on the fate of orally administered drugs which normally undergo a high presystemic elimination is as yet ill-defined. Experiments, therefore, were designed in four nonanesthetized dogs with mephenytoin as model compound. The drug was administered p.o. or i.v., and throughout an 8-hr period ethanol (100 mg kg-1 hr-1) or saline was infused according to a cross-over design. Concentrations of mephenytoin and its main metabolites, nirvanol and p-hydroxymephenytoin, were determined by gas-liquid chromatography. In experiments with oral mephenytoin administration and ethanol infusion, mephenytoin peak plasma concentrations were elevated by 87.0 +/- 15.2% (S.E.M.) (P less than .005, n = 4). Correspondingly, the average area under the plasma concentration time curve was increased to 229% of control (P less than .005). Ethanol also reduced metabolite formation; the area under the plasma concentration time curve for nirvanol was reduced by 40% (P less than .005). Urinary output of nirvanol was diminished to 51% and of p-hydroxymephenytoin to 73% (P less than .05, n = 12). It is concluded that drug ethanol interactions may be particularly prominent for orally administered drugs which normally are subject to a high presystemic elimination. This mechanism might be a clinically relevant cause for ethanol related drug toxicity.

[Polarographic determination of some phenylsubstituted anticonvulsants]. / Polarographische Bestimmung einiger phenylsubstituierter Antikonvulsiva

A method is described to determine the anticonvulsive drugs phenobarbital, phenytoin, mephenytoin, methylphenobarbital and primidone. A serum extract is nitrated, separated by thin-layer chromatography, and the nitro compounds are determined by polarography. The rates of recovery are: phenobarbital 81%, phenytoin 79%, mephenytoin 80%, methylphenobarbital 86% and primidone 84%. The sensitivity limits range from 3.5 mug/ml plasma for phenytoin to 5.5 mug/ml for mephenytoin and methylphenobarbital. This method might be useful not only for determination of therapeutic blood levels but also for toxicology because it saves time and the expenditure of work is small. The mean deviation for mononitrated anticonvulsive drugs is +/- 2.8% (for 50 mug/ml) and +/- 11.6% (for 10 mug/ml). For phenytoin being dinitrated, the values are +/- 0.6% and +/- 7.5% for 50 mug and 5 mug, respectively). We determined blood levels of out-patients containing phenobarbital and phenytoin besides other substances. Having once established calibrating curvers internal or external standards are not required.

Flash-heater ethylation of some antiepileptic drugs.

We describe a modification of the MacGee method [Anal. Chem. 42, 421 (1970)] for rapid determination of phenytoin (diphenylhydantoin) in plasma by gas-liquid chromatography, in which an ethylaing reagent is used instead of the more common methylating reagents. With this modification, several N-methylated antiepileptic drugs can be separated from their demethylated metabolites. Our results agree well with those of Butler and Waddell [Neurology 8, 106 (1958)], who showed that in patients receiving the N-methylated compounds mephenytoin and mephobarbital, the N-demethylated products, 5-ethyl-5-phenylhydantoin and phenobarbital are found in higher concentrations in plasma than are their respective parent drugs. The method is also useful for routine determinations of phenobarbital, primidone, and phenytoin in serum, cerebrospinal fluid, or saliva.

Pharmacokinetics of R-enantiomeric normephenytoin during chronic administration in epileptic patients.

Stereoselective metabolism has been demonstrated for mephenytoin (MHT), R-MHT being demethylated to the pharmacologically active metabolite 5-phenyl-5-ethylhydantoin (PEH; nirvanol), and S-MHT undergoing aromatic hydroxylation to 4-OH-MHT, with formation of an intermediate arene oxide metabolite. PEH is responsible for the therapeutic effect, whereas 4-OH-MHT is rapidly eliminated by the kidneys. The arene oxide metabolite may have implications in MHT toxicity. The metabolism of PEH is also stereospecific. In the present study, the R-enantiomer of PEH (R-PEH; R-normephenytoin) was administered chronically during 8 weeks to four epileptic patients, as a single dose every 3 days. The half-lives of R-PEH ranged from 77.7 to 175.8 h, and correlated closely with the creatinine clearance. Mean urinary recovery of R-PEH was 86.6% of the dose at steady state, with 4-OH-PEH accounting for only 5%. This indicates that, unlike Nirvanol (a racemic mixture of R- and S-PEH), R-PEH is only minimally metabolized, even after several weeks of treatment and despite potential enzymatic autoinduction and heteroinduction by other antiepileptic drugs. Complete blood counts and liver function tests revealed no alteration, and no other adverse effects were noted. If arene oxide intermediate metabolites are indeed involved in the toxicity of MHT and nirvanol, R-PEH may represent a safer alternative.

The N-demethylation of imipramine correlates with the oxidation of S-mephenytoin (S/R-ratio). A population study.

The metabolism of imipramine was investigated in 106 healthy volunteers, all having a sparteine metabolic ratio (MR) of 0.2-0.5 and hence classified as extensive metabolisers. Each subject was given a single oral dose of 25 mg imipramine hydrochloride and blood for assays of imipramine and metabolites was collected 3 h thereafter. The desipramine/imipramine ratio and the 2-OH-desipramine/2-OH-imipramine ratio in plasma, reflecting the demethylation of imipramine and 2-OH-imipramine, respectively, showed significant negative correlations with the mephenytoin S/R ratio (Spearman rank correlation) (rs): -0.46, P < 0.00002 and -0.41, P < 0.00002). No correlations were found between the 2-hydroxylation of imipramine or desipramine and the mephenytoin S/R. These findings confirm those of an earlier panel study showing that the demethylation of imipramine and 2-OH-imipramine cosegregates in part with the mephenytoin oxidation polymorphism.