Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics.

Although the majority of oxidative metabolic reactions are mediated by the CYP superfamily of enzymes, non-CYP-mediated oxidative reactions can play an important role in the metabolism of xenobiotics. The (major) oxidative enzymes, other than CYPs, involved in the metabolism of drugs and other xenobiotics are: the flavin-containing monooxygenases, the molybdenum hydroxylases (aldehyde oxidase and xanthine oxidase), the prostaglandin H synthase, the lipoxygenases, the amine oxidases (monoamine, polyamine, diamine and semicarbazide-sensitive amine oxidases) and the alcohol and aldehyde dehydrogenases. In a similar manner to CYPs, these oxidative enzymes can also produce therapeutically active metabolites and reactive/toxic metabolites, modulate the efficacy of therapeutically active drugs or contribute to detoxification. Many of them have been shown to be important in endobiotic metabolism, and, consequently, interactions between drugs and endogenous compounds might occur when they are involved in drug metabolism. In general, most non-CYP oxidative enzymes appear to be noninducible or much less inducible than the CYP system, although some of them may be as inducible as some CYPs. Some of these oxidative enzymes exhibit polymorphic expression, as do some CYPs. It is possible that the contribution of non-CYP oxidative enzymes to the overall metabolism of xenobiotics is underestimated, as most investigations of drug metabolism in discovery and lead optimisation are performed using in vitro test systems optimised for CYP activity.

Effect of levetiracetam on the pharmacokinetics of adjunctive antiepileptic drugs: a pooled analysis of data from randomized clinical trials.

The purpose of this study was to determine the influence of levetiracetam on the steady-state serum concentrations of other commonly used antiepileptic drugs (AEDs). Serum AED concentrations were measured at baseline and after adjunctive therapy with levetiracetam (1000-4000 mg/day) or placebo in four phase III trials in patients with refractory partial epilepsy receiving stable AED dosages. The data were pooled, and repeated measures covariance analysis was used to calculate the ratio (and 90% confidence intervals) of the geometric mean serum drug concentrations during adjunctive levetiracetam therapy relative to baseline. Levetiracetam did not increase or decrease mean steady-state serum concentrations of carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. For each of these AEDs, the 90% confidence interval of the geometric mean drug concentrations ratio was included within the 80-125% bioequivalence range. Serum concentrations of these AEDs did not change over time after adjunctive levetiracetam therapy, irrespective of the dosage of levetiracetam used. For vigabatrin, there was no evidence for a significant change in serum drug concentration after the addition of levetiracetam, but the number of observations was too small for the limits of the confidence interval to fall within the 80-125% range. Thus, adjunctive therapy with levetiracetam does not influence the steady-state serum concentrations of concomitantly administered carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. Consequently, no need for adjusting the dosages of these AEDs is anticipated when levetiracetam is added on or removed from a patient's therapeutic regimen.

Pharmacokinetics and metabolism of 14C-levetiracetam, a new antiepileptic agent, in healthy volunteers.

The absorption, disposition and metabolism of levetiracetam, a new antiepileptic drug, have been investigated after a single oral dose of the (14)C-labelled molecule administered to male healthy volunteers. As chiral inversion can occur during drug metabolism, the chiral inversion of levetiracetam and/or of its major metabolite produced by hydrolysis (the corresponding acid) was also investigated. Finally, the in vitro hydrolysis of levetiracetam to its major metabolite and the inhibition of this reaction in human blood have been studied. Levetiracetam was very rapidly absorbed in man, with the peak plasma concentration of the unchanged drug occurring at 0.25-0.50 h. The unchanged drug accounted for a very high percentage of plasma radioactivity (97-82%) at all the times measured, i.e. until 48 h after administration. The apparent volume of distribution of the compound was close (0.55-0.62 l/kg) to the volume of total body water. Total body clearance (0.80-0.97 ml/min/kg) was much lower than the nominal hepatic blood flow. The plasma elimination half-life of the unchanged drug varied between 7.4 h and 7.9 h. Plasma to blood ratio of total radioactivity concentrations was 1.1-1.3, showing that radioactivity concentrations were similar in blood cells and plasma. The balance of excretion was very high in all four volunteers. The predominant route of excretion was via urine, accounting for a mean of 95% of the administered dose after 4 days. Two major radioactive components were present in urine, the unchanged drug and the acid obtained by hydrolysis, accounting for 66% and 24% of the dose after 48 h, respectively. Hydrolysis of levetiracetam in human blood followed Michaelis-Menten kinetics with Km and V(max) values of 435 microM and 129 pmol/min/ml blood, respectively. Among the inhibitory agents investigated in this study, only paraoxon inhibited levetiracetam hydrolysis (92% inhibition at 100 microM). Oxidative metabolism occurred in man, although it accounted for no more than 2.5% of the dose. There was no evidence of chiral inversion.

Effects of antiepileptic comedication on levetiracetam pharmacokinetics: a pooled analysis of data from randomized adjunctive therapy trials.

PURPOSE: To assess the influence of commonly used antiepileptic drugs (AEDs) on levetiracetam pharmacokinetics at steady state. METHODS: Plasma levetiracetam concentrations at steady state were determined by capillary gas chromatography in 590 epilepsy patients included in phase III trials and treated with doses of 1000-4000 mg per day in two divided daily doses. The data were pooled and kinetic parameters estimated by repeated measurement covariance analysis on log-transformed dose-adjusted concentrations (regression line as function of time elapsed since last dose). RESULTS: Estimated pharmacokinetic values, normalized to a dose of 1 mgkg(-1) b.i.d., were: concentration at 1h (C(1h)) 2.1 microgram ml(-1), concentration at 12h (C(12h)) 0.8 microgram ml(-1), area under the curve from 0 to 12h (AUC(0-12h)) 17.1 microgram ml(-1)h, half-life (t(1/2)) 8.1h, and apparent oral clearance (CL/F) 0.97 mlmin(-1)kg(-1). Parameters were similar between genders and among dosage subgroups. Compared with patients receiving comedication not considered to affect drug metabolizing enzymes (gabapentin, lamotrigine, vigabatrin), levetiracetam concentrations and t(1/2) tended to be lower in patients receiving enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital, primidone) and higher in patients receiving valproic acid, but the differences were modest. CONCLUSIONS: Estimated parameters were dose independent, comparable to those from smaller scale studies and not affected to any major extent by gender or comedication with other AEDs. Based on this, no need is anticipated for adjusting levetiracetam dosage according to type of concomitantly prescribed AEDs.

Blood distribution of levocetirizine, a new non-sedating histamine H1-receptor antagonist, in humans.

The aim of the present study was to determine (1) the extent of levocetirizine binding to human blood cells, plasma and individual plasma proteins; (2) the parameters for levocetirizine binding to individual plasma proteins both at their physiological concentrations and, for human serum albumin (HSA), at a lower saturating concentration; and (3) to simulate levocetirizine distribution in human blood using the information obtained at physiological haematocrit (H) for blood cells and at physiological concentrations for individual plasma proteins. The nature of the main binding sites of HSA, i.e. site I (warfarin) and site II (diazepam), preferentially involved in levocetirizine binding was also investigated. Over the range of therapeutic concentrations and multiples thereof, levocetirizine is extensively bound to blood components, the free fraction remaining constant (6.45%) and the fraction bound to blood cells and to plasma proteins accounting for 27.43 and 66.11%, respectively. The binding of levocetirizine to HSA in the presence of physiological concentrations of non-esterified fatty acids (NEFAs) is the main interaction of levocetirizine in blood (50.68% of overall blood binding). This interaction is fatty acid sensitive, with decreasing concentrations of NEFA increasing the amount of bound drug and vice versa. Levocetirizine is also bound to alpha1-acid-glycoprotein and high-density lipoproteins (5.17 and 6.89% of overall blood binding, respectively). The displacement of levocetirizine by diazepam is consistent with the binding of this drug to HSA at site II, as diazepam is a specific marker for this site. The binding of levocetirizine to HSA at site II being characterized by a low association constant, other drugs sharing the same site with high association constants cannot displace levocetirizine except at very high plasma concentrations. In any case, at therapeutic concentrations of levocetirizine and at physiological protein concentrations, the observation that none of the levocetirizine binding proteins is saturated suggests that very little or no variation of the free fraction will occur although a different distribution of its bound forms is possible.