PURPOSE: This study was conducted to determine whether vigabatrin affects in vivo indices of hepatic microsomal enzyme activity and the pharmacokinetics of steroid oral contraceptives in healthy subjects. METHODS: Under double-blind conditions, 13 female healthy volunteers received, in random order and with a washout interval of > or = 4 weeks, two oral 4-week treatments with vigabatrin (VGB) (maintenance dosage, 3,000 mg daily) and placebo, respectively. The clearance and half-life of antipyrine (a broad marker of drug oxidation capacity), the urinary excretion of 6-beta-hydroxycortisol (a selective marker of cytochrome CYP3A-mediated oxidation), and the activity of serum gamma- glutamyltransferase (a nonspecific index of microsomal enzyme activity) were determined after 3 weeks of each treatment. The single-dose kinetics of a combined oral contraceptive containing 30 micrograms ethinyl estradiol and 150 micrograms levonorgestrel were also determined after 3 weeks of treatment by specific radioimmunologic assays. RESULTS: VGB treatment had no influence on antipyrine clearance (28 +/- 5.6 vs. 30 +/- 4.5 ml/h/kg on placebo), antipyrine half-life (15.5 +/- 3.5 vs. 14.1 +/- 2.1 h), urinary 6-beta-hydroxycortisol excretion (488 +/- 164 vs. 470 +/- 228 nmol/ day), 6-beta- hydroxycortisol-to-cortisol concentration ratio (6.8 +/- 3.1 vs. 6.1 +/- 3.1) and serum gamma-glutamyltransferase activity (12 +/- 3 vs. 11 +/- 3 IU/L). No difference in pharmacokinetic parameters between VGB and placebo sessions were found for ethinyl estradiol (half-life, 12.5 +/- 3.2 vs. 13.9 +/- 3.2 h; AUC, 874 +/- 301 vs. 939 +/- 272 ng/ L/h) and levonorgestrel (half-life, 17.7 +/- 5.2 vs. 23.1 +/- 9.8 h; AUC, 27.5 +/- 9.6 vs. 30.0 +/- 12.0 micrograms/L/h). Two subjects, however, showed a 50 and a 39% reduction in ethinyl estradiol AUC during VGB treatment. CONCLUSIONS: At therapeutic dosages, VGB did not modify in vivo indices of hepatic microsomal enzyme activity and did not interfere significantly with the CYP3A-mediated metabolism of ethinyl estradiol and levonorgestrel. Based on these data, VGB is unlikely to affect consistently the efficacy of steroid oral contraceptives or interact pharmacokinetically with drugs that are eliminated mainly by oxidative pathways, particularly those involving cytochrome CYP3A

Summary: Generally, the efficacy of an anticonvulsant drug is a function of the intensity of the seizure process and the drug concentration in plasma and tissues. Because of the variability of the seizure process among individuals, a universally effective drug plasma level is not to be expected. Rather a 'desirable' plasma level range for each drug can be defined, the lower limits being those levels above which the majority of patients are well controlled, the upper limits being determined by the onset of drug intoxication. With the onset of administration of anticonvulsants in average doses, the maximum plasma levels and effect are reached only after several days or with some drugs, after several weeks of therapy. The lag time can be reduced with loading doses in the case of phenytoin or phenobarbitone (2 to 3 times the usual dose). For maintenance therapy phenytoin and phenobarbitone may be given in a single daily dose without marked fluctuations in the plasma levels. Some variations in the plasma levels relative to particular doses do occur, but in the majority of patients predictable ranges of plasma levels relative to doses can be defined. Marked deviations from these expected ranges are however, not infrequent. Low levels are most frequently caused by patients' failure to take the drug regularly. Rare causes for low plasma levels are malabsorption of the drug, or unusually rapid drug metabolism or elimination. High levels may be caused by ingestion of greater than the prescribed dose, by impaired drug metabolism or elimination (genetic or constitutional), or because of interactions with other drugs. Elevation of phenytoin plasma level to the toxic range has been caused by a number of drugs, most predictably with disulfiram, sulthiame and isoniazid. When the interfering drug cannot be discontinued, the phenytoin dosage must be reduced and a new dose titrated using the plasma level as the indicator. In the treatment of petit mal, the order of preference of drugs is based on efficacy and safety, with ethosuximide the drug of choice, followed in order by trimethadione, para-methadione, methsuximide and phensuximide. In grand mal and focal epilepsies, phenytoin and phenobarbitone are the best understood and successful drugs. Primidone is also very effective. Carbamazepine can be used as an alternative. A number of other agents are available for use in combination with the prime drugs in highly refractory cases, or alone when the major drugs are contra-indicated. ACTH, or if this fails, diazepam or nitrazepam, can be used to abolish seizures in infantile spasms. Diazepam is the drug of choice in status epilepticus; given intravenously in status grand mal, or intramuscularly or intravenously in status petit mal and status focal seizures. Adverse effects of anticonvulsants can be divided into three groups: those which are a result of intoxication and which are related to elevated plasma levels. These include nystagmus, sedation and unsteadiness, and are usually, but not inevitably, a consequence of overdosage. The second category includes the side-effects, which occur as by-products of the pharmacological action of the drugs when used in the usual doses and with plasma levels in the desirable range. They may be more severe with higher doses. Frequent among these are gum hypertrophy with phenytoin, photophobia with trimethadione and depression of folate with hydantoins and barbiturates. Idiosyncratic reactions comprise the third category of unwanted effects; these are unpredictable, are unrelated to dose or plasma level and presumably occur on an allergic basis. Most frequent are skin rashes, and most dangerous are blood dyscrasias. The dysmorphogenic effects, the effects on the pregnant mother and on the newborn are reviewed.

Over 700 alleged OC/drug interactions were reported for antituberculous drugs, other antibiotics, anticonvulsants, antidepressants, and analgesics. Fewer than ten reports of OC/drug interactions were found involving antihistamines, thyroid hormone, vitamin C, antacids, ulcer medication, or diuretics. These may represent a set of OC/drug interaction problems that need to brought into medical awareness. Pregnancy is the first event reported when OCs appear to interact with another drug. However, menstrual disturbances are reported more often. BTB is the most frequently reported menstrual disturbance: it has been considered a warning signal that OC efficacy may be compromised. In such circumstances, contraceptive backup may be warranted. Reports of interference with OC efficacy have been most common for drugs used to treat tuberculosis, epilepsy, and depression, so patients and their physicians should be aware of potential problems. However, the average woman is more likely to encounter antibiotics, analgesics, and antihistamines, and current package inserts contain appropriate warnings. In recent years, prescriptions for low-estrogen OCs have outnumbered those for high-dose preparations. Many physicians became concerned that there was an increased risk of OC drug failure with the low-dose products. The database does not seem to suggest that this has happened. The dose of estrogen is not correlated with total adverse experience reports, time of appearances of the first adverse experience reports, or rate of reporting of the interactions. Likewise, reports of potential interactions with menstrual disturbances are not correlated with lower estrogen doses in OCs. There is, however, an association between low-estrogen OCs and recently reported pregnancies attributed to OC/drug interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

There is considerable variation in opinion about the importance of drug interactions between the combined oral contraceptive pill (COCP) and broad-spectrum antibiotics. Clinical practice varies widely, especially between doctors in Europe and those in the US. Rifampicin and griseofulvin induce hepatic enzymes and do appear to have a genuine interaction with the COCP, leading to reduced efficacy. The situation with the broad-spectrum antibiotics is less clear. There are relatively few prospective studies of the pharmacokinetics of concurrent COCP and antibiotic use and few, if any, demonstrate a convincing basis for any reduced contraceptive efficacy. There is evidence, however, that variable contraceptive steroid handling could make some women, at some times, more susceptible to COCP failure. Given the serious consequences of unwanted pregnancy, the cautious approach of using additional or alternative contraception during short courses of broad-spectrum antibiotics and the initial weeks of long-term antibiotic administration may be justified to safeguard the few unidentifiable women who may be at risk. Conflicting opinion and advice is potentially confusing to both professionals and patients, and instructions for additional precautions during and after concurrent COCP and antibiotic use are complicated. Many women are ignorant of, or confused about, the circumstances that can cause OC to fail. Health professionals who prescribe the COCP must continue to strive to educate women about the mode of action and about the times when there is the greatest danger of failure. Professionals who feel that concurrent antibiotic use represents a real threat to contraceptive efficacy of the COCP should be prepared to present the advice for additional contraceptive precautions in a simple and consistent way, backed up with written information and reinforced at regular intervals

Many drug interactions can be demonstrated, but only a few are so clinically significant that they necessitate adjusting drug dosages. The same drug combination may produce changes of variable extent or direction in different individuals. The reasons for this variability include genetic control of the rate and inducibility of drug metabolism, and environmental factors such as contact with chemicals. Among antimicrobial agents, chloramphenicol may cause accumulation of phenytoin (PHT) and phenobarbital (PB), and isoniazid may cause PHT, carbamazepine (CBZ), and primidone (PRM) to accumulate. Erythromycin may cause accumulation of CBZ. Among anti-ulcer agents, antacids may reduce PHT concentration while cimetidine may cause accumulation of PHT, CBZ, and diazepam (DZP). Salicylates displace strongly binding drugs such as PHT, DZP, or valproate (VPA) from the binding sites in plasma proteins, which may lead to some decline of the total plasma level with an increase in the unbound drug percentage. Conversely, anticonvulsants may influence the dosage requirements of oral anticoagulants by inducing their metabolism. Failures of oral contraceptives have been attributed to anticonvulsants in some patients. Probably the most predictable interaction that necessitates dosage adjustment is accumulation of PB caused by VPA. Intentional inhibition of PRM metabolism by nicotinamide serves as an example of attempts to utilize an interaction for improved therapeutic effect

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

Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial beta-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required

Patients taking oral contraceptive steroids (OCS) are known to suffer contraceptive failure while taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine. We have studied the single dose kinetics of ethinyloestradiol (EE2); 50 micrograms, and levonorgestrel (Ng); 250 micrograms in groups of women before and 8-12 weeks after starting therapy with phenytoin (n = 6) and carbamazepine (n = 4). The area under the plasma concentration-time curve (AUC) was measured over a 24 h period for each steroid and significant reductions were seen with both anticonvulsants. Phenytoin reduced the AUC for EE2 from 806 +/- 50 (mean +/- s.d.) to 411 +/- 132 pg ml-1 h (P less than 0.05) and for Ng from 33.6 +/- 7.8 to 19.5 +/- 3.8 ng ml-1 h (P less than 0.05). Carbamazepine reduced the AUC for EE2 from 1163 +/- 466 to 672 +/- 211 pg ml-1 h (P less than 0.05) and for Ng from 22.9 +/- 9.4 to 13.8 +/- 5.8 ng ml-1 h (P less than 0.05). These changes are compatible with the known enzyme inducing effects of phenytoin and carbamazepine. Patients taking these anticonvulsants will need to be given increased doses of OCS (equivalent to 50-100 micrograms EE2 daily) to achieve adequate contraceptive effects.