Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin.

Seizure control and plasma concentrations of antiepileptic drugs (AEDs) were determined in a prospective, population-based study of 93 pregnancies (cases) of 70 patients with epilepsy. Seventy-seven cases were treated with monotherapy, which in 70 cases consisted of carbamazepine (CBZ) or phenytoin (PHT). Dosage was kept constant unless poor seizure control prompted an increase. Plasma concentrations were determined at monthly intervals throughout pregnancy and compared with baseline levels obtained at least 10 weeks postpartum. Both free and total CBZ and PHT concentrations were analyzed. Seizure frequency during pregnancy for the group as a whole was not different as compared with the 9 pregestational months and was unaltered or improved in 85% of cases. Total CBZ concentration was slightly lower during the third trimester as compared with baseline, whereas free concentration was unchanged. In contrast, PHT levels decreased steadily as pregnancy progressed. Total plasma concentration was 39% of baseline during the third trimester, whereas free PHT concentration decreased far less, being 82% of baseline level during the third trimester. No clear-cut relation could be demonstrated between seizure control and plasma concentrations, which may be explained by the limited changes in free AED concentrations and the small number of cases with an increased seizure frequency. Our results indicate that total plasma concentrations may be misleading and that monitoring of free concentrations, in particular of PHT concentrations, may be advantageous during pregnancy.

Disposition of carbamazepine and phenytoin in pregnancy.

Free and total plasma concentrations of phenytoin (PHT) and carbamazepine (CBZ) and its active metabolite carbamazepine-10, 11-epoxide (CBZ-E) were determined in a prospective study of 86 pregnant epileptic women. The pharmacokinetics of PHT and CBZ during the three trimesters were compared with kinetics at least 10 weeks postpartum. Plasma clearance and unbound CBZ clearance were slightly decreased during the last trimester. Total and free plasma CBZ-E concentrations did not change significantly during pregnancy. Plasma PHT clearance, on the other hand, increased from the first trimester. A less pronounced increase was observed for clearance of unbound PHT; the increase was statistically significant only during the third trimester.

Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: increased plasma levels of the reduced metabolite in poor metabolizers.

We have previously shown that the disposition of haloperidol is decreased in poor (PM) compared to extensive (EM) metabolizers of debrisoquine. We now report that the plasma levels of the reduced metabolite of haloperidol, after a single 2- or 4-mg oral dose of the parent drug, are significantly higher in PM than in EM of debrisoquine. As PM have higher concentrations of haloperidol than EM, more of the reduced metabolite should be formed, since the formation of reduced haloperidol from haloperidol seems to be independent of the debrisoquine hydroxylase (cytochrome P4502D6) activity. Another reason to explain the increased metabolite levels in PM may be a decreased reoxidation of the reduced metabolite to haloperidol, as this reaction is catalyzed by cytochrome P4502D6. A third reason might be that reduced haloperidol is transformed to other metabolites by this enzyme.

Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype.

To investigate the importance of genetic factors for the regulation of haloperidol metabolism, we studied the disposition of a single oral dose of this drug in a panel of six extensive (EM) and six poor (PM) metabolizers of debrisoquine. PM eliminated haloperidol significantly slower than EM, the plasma half-life being longer (mean 29.4 +/- S.D. 4.2 and 16.3 +/- 6.4 h; p less than 0.01) and the clearance lower (1.16 +/- 0.36 and 2.49 +/- 1.31 L/h/kg; p less than 0.05). A 4-mg dose of haloperidol was given to the first three PM, but all three developed side effects, and a 2-mg dose had to be given to the next three PM subjects. All EM received 4 mg haloperidol. The disposition of haloperidol is thus associated with the genetically determined capacity to hydroxylate debrisoquine. PM of debrisoquine (7% of Caucasian populations) might, therefore, on common doses of haloperidol, achieve high plasma concentrations and thereby have an increased risk of side effects. At the other extreme, very rapid metabolizers may need increased doses of haloperidol.

Disposition of the neuroleptic zuclopenthixol cosegregates with the polymorphic hydroxylation of debrisoquine in humans.

The pharmacokinetics of a single oral dose of the neuroleptic drug zuclopenthixol (10 or 6 mg) was studied in 6 extensive and 6 poor metabolizers of debrisoquine. The peak plasma concentrations of zuclopenthixol did not differ between the phenotypes, whereas the plasma elimination half-life was significantly longer in poor than in extensive metabolizers (29.9 +/- 6.6 vs 17.6 +/- 6.9 h). Accordingly, the total oral plasma clearance was lower in poor than in extensive metabolizers (0.78 +/- 0.27 vs 2.12 +/- 0.65 1/h/kg). Ten of the volunteers had previously participated in a similar study in which the kinetics of perphenazine, another neuroleptic drug, were studied in poor and in extensive metabolizers of debrisoquine. There was a significant correlation between the oral clearance of perphenazine and that of zuclopenthixol among these 10 subjects. The study indicates that the disposition of zuclopenthixol, as well as that of perphenazine, is related to the genetically determined capacity to hydroxylate debrisoquine. The significance of this polymorphism for the clinical use of neuroleptics is discussed.

Lower 3H-imipramine binding in platelets from untreated depressed patients compared to healthy controls.

3H-Imipramine binding in platelets was measured in 63 severely depressed hospitalized patients, who had been drug free (with the exception of moderate doses of benzodiazepines) for at least 1 month, and in 53 healthy control subjects of comparable age and sex distribution. Bmax of 3H-imipramine binding was significantly lower in the depressed subjects (1012 +/- SD 295 vs. 1123 +/- SD 178 fmole/mg protein). Depressed patients who had attempted suicide by violent means tended to have higher Bmax than nonviolent attempters.

Weak binding of 10-hydroxymetabolites of nortriptyline to rat brain muscarinic acetylcholine receptors.

The relative affinities of nortriptyline (NT) and its 10-hydroxymetabolites to rat brain muscarinic acetylcholine receptors have been determined by competition with 3H-quinuclidinyl benzilate binding. It is shown that the major NT metabolite, E-10-OH-NT, has only 1/18 the affinity of NT for the muscarinic receptor. Since this metabolite is equipotent to NT in inhibiting neuronal noradrenaline uptake, it is suggested that it might be of clinical value as an antidepressant by virtue of having less anticholinergic side-effects than NT itself.

Protein binding of anthraquinone glycosides, with special reference to adriamycin.

The binding of anthraquinone glycosides (adriamycin, adriamycinol, daunorubicin, daunorubicinol, and 4'epiadriamycin) to human serum albumin and human plasma has been studied by equilibrium dialysis. About 62% of adriamycin was bound to human serum albumin (45 g/l). Only minor variations in the degree of binding were observed between the anthraquinone glycosides. The binding degree of adriamycin in plasma from cancer patients was not significantly different from that observed in healthy volunteers, the fraction of free adriamycin being 24.56% +/- 4.51%, and 27.67% +/- 2.78%, respectively. The plasma albumin concentration was significantly lower in cancer patients than in the healthy volunteers (26.90% +/- 5.88% and 39.24% +/- 1.74%, respectively). In cancer patients the fraction of free adriamycin decreased with increasing plasma albumin concentration.