Oxcarbazepine (OCBZ) is a new antiepileptic drug (AED) structurally related to carbamazepine (CBZ) but differing in several important aspects, notably metabolism and induction of metabolic pathways. Consequently, OXCB has fewer drug-drug interactions compared with CBZ. Absorption of OCBZ is rapid and complete. In animals it is responsible for the pharmacological effect. In humans, however, the parent compound is rapidly and extensively metabolized to a monohydroxy derivative (MHD), which is responsible for the therapeutic effect. Exposure to the MHD increases dose proportionally, and steady state is achieved after only three or four doses in a twice-daily regimen. When given with food, systemic exposure to MHD increases by about 17%. MHD is eliminated with a half-life of about 8-10 h. About 27% of the dose is recovered in the urine as unchanged MHD and a further 49% as a glucuronide conjugate of MHD. Results suggest that the kinetics of OCBZ should not be affected by impaired liver function. Impaired kidney function does not affect the kinetics of MHD; the glucuronide conjugate will, however, accumulate in these patients. The conversion of OCBZ to MHD is catalyzed by reductase enzymes, which are not subject to induction. Furthermore, OCBZ itself does not appear to induce the cytochrome P-450 family in general, although it does induce the P-450 IIIA subfamily, which is responsible for the metabolism of estrogens and the dihydropyridine calcium-channel blockers (e.g., nifedipine, felodipine). In patients, linear and dose-proportional kinetics with no autoinduction of metabolism simplify OCBZ dosage adjustment.

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AimsTo investigate the effects of aliskiren, an oral renin inhibitor, on the pharmacokinetics and pharmacodynamics of warfarin. MethodsIn a single-blind, placebo-controlled, randomized, two-period crossover study, 15 healthy male and female subjects received a single oral dose of 25 mg racemic warfarin twice, once in the morning of the 8th day of treatment with 150 mg aliskiren and once at the same time point during treatment with placebo. Blood samples were collected for the measurement of prothrombin time (PT) and activated thromboplastin time (aPTT) and for determination of plasma concentrations of (R)-and (S)-warfarin. ResultsAliskiren treatment had no effect on the blood coagulation parameters (PT, INR and aPTT). The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of aliskiren for (R)-and (S)-war farin were C max 0. 89 (0.82, 0.96) and 0.88 (0.80, 0.97), AUC(0, • ) 1.00 (0.94, 1.07) and 1.06 (0.96, 1.16) and t 1/2 0.99 (0.92, 1.07) and 1.05 (0.96, 1.14). ConclusionsMultiple doses of aliskiren had no detectable effect on the pharmacokinetics or pharmacodynamics of a single dose of warfarin in healthy subjects.

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The absorption, biotransformation and elimination of sulfinpyrazone, 1,2-diphenyl-3,5-dioxo-4-(2'-phenylsufinylethyl)-pyrazolidine, have been studied by administration of single 200 mg oral doses of a 14C-labelled preparation to two male volunteers. Absorption from the gastro-intestinal tract was rapid and complete and the plasma concentration of unchanged drug reached maximum values of 22.67 and 13.04 mug/ml, respectively, after 1 - 2 hours. The elimination half-life in the two subjects, calculated from the decline between 3 and 8 hours, was 2.7 and 2.2 hours. The integrated concentration of unchanged sulfinpyrazone in plasma, estimated from the area under the concentration curves (AUC), was almost as high as that of total 14C-substances, so the proportion of metabolized drug in plasma was low. In no case did the AUC of the three specifically determined metabolites. i.e. the sulphone G 31 442, the "para-hydroxy"=compound G 32 642 and the "4-hydroxy"- compound GP 52 097, exceed 4% of the sulfinpyrazone value. More than 95% of whole blood radioactivity was confined to plasma. The oral dose was rapidly and completely excreted, since within 4 days more than 95% was recovered, 85% from urine and 10% from faeces. A large proportion of the dose was excreted as unchanged drug in the two volunteers: 51 and 54% of total urinary radioactivity was present as sulfinpyrazone; 8.2 and 8.8% was present as "para-hydroxy"-metabolite, 2.7 and 3.0% as sulphone-metabolite, and 0.6 and 0.8% as "4-hydroxy"-metabolite. About 30% of urinary radioactivity consisted of highly polar metabolites. Spectroscopy of them showed that they were the C-beta-glucuronides of sulfinpyrazone (28%) and the corresponding sulfone (2%). In these metabolites the C(4) of the pyrazolidine ring was directly attached to glucuronic acid, and thus they represent a new type of biosynthetic conjugate.