FAD-dependent enzymes involved in the metabolic oxidation 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. Among the major oxidative enzymes, other than CYPs, involved in the oxidative metabolism of drugs and other xenobiotics, the flavin-containing monooxygenases (FMOs), the molybdenum hydroxylases [aldehyde oxidase (AO) and xanthine oxidase (XO)] and the FAD-dependent amine oxidases [monoamine oxidases (MAOs) and polyamine oxidases (PAOs)] are discussed in this minireview. 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 (e.g. XO, MAOs), and, consequently, interactions between drugs and endogenous compounds might occur when they are involved in drug metabolism. In general, most non-CYP oxidative enzymes (e.g. FMOs, MAOs) appear to be noninducible or much less inducible than the CYP system. Some of these oxidative enzymes exhibit polymorphic expression, as do some CYPs (e.g. FMO3). 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 have been performed using experimental conditions optimised for CYP activity, although in some cases the involvement of non-CYP oxidative enzymes in xenobiotic metabolism has been inferred from not sufficient experimental evidence.

Defence mechanisms of olfactory neuro-epithelium: mucosa regeneration, metabolising enzymes and transporters.

The olfactory neuro-epithelium is highly sensitive to chemicals and its direct microbiological environment. It also plays a role as an interface between the airways and the nervous system, and so it has developed several defence instruments for rapid regeneration or for the detoxification of the immediate environment. This review illustrates three of these defence mechanisms: regeneration of the epithelium, local production of metabolising enzymes and xenobiotic transporters. Toxicants can inflict damage by a direct toxic response. Alternatively, they may require metabolic activation to produce the proximate toxicant. In addition to detoxifying inhaled and systemically derived xenobiotics, the local olfactory metabolism may fulfil multiple functions such as the modification of inhaled odorant, the modulation of endogenous signalling molecules and the protection of other tissues such as the CNS and lungs from inhaled toxicants. Finally, the permeability of nasal and olfactory mucosa is an important efficacy parameter for some anti-allergic drugs delivered by intranasal administration or inhalation. Efflux or update transporters expressed in these tissues may therefore significantly influence the pharmacokinetics of drugs administered topically.

Stereoselective renal tubular secretion of levocetirizine and dextrocetirizine, the two enantiomers of the H1-antihistamine cetirizine.

Competition for uptake and/or efflux transporters can be responsible for drug interactions. Cetirizine is mainly eliminated unchanged in urine through both glomerular filtration and tubular secretion. The aim of this study was to investigate whether the eutomer, levocetirizine, and the distomer, dextrocetirizine, have a similar tubular secretion. The renal clearance associated with tubular secretion was calculated from the renal clearance of levocetirizine and dextrocetirizine obtained in a study in healthy volunteers. The values of the unbound fraction in plasma were obtained in an in vitro study of the binding of (14)C-cetirizine and (14)C-levocetirizine to human plasma proteins using equilibrium dialysis and chiral high-performance liquid chromatography (HPLC) with on-line liquid scintillation counting. The unbound fraction was 0.074 for levocetirizine and 0.141 for dextrocetirizine. The tubular secretion of dextrocetirizine (44.5 mL/min) is higher than that of levocetirizine (23.1 mL/min), which may have consequences for drug interactions at the renal level. The higher tubular secretion for dextrocetirizine may be due to the higher free fraction available for secretion or to a higher affinity for (a) renal transporter(s) mediating the secretion pathway.

Factors affecting the relative importance of amine oxidases and monooxygenases in the in vivo metabolism of xenobiotic amines in humans.

The monooxygenases and the amine oxidases (AOs) are the major enzyme systems involved in vivo in the oxidative metabolism of xenobiotic amines in humans. With the exception of the inhibition of the metabolism of tyramine ingested by subjects taking inhibitors of MAO-A or of both MAO-A and -B, which has been extensively investigated, the involvement of the monoamine oxidases in xenobiotic amine metabolism (drugs in particular) has been largely neglected. Furthermore, with the exception of amlodipine, there have been essentially no studies on the metabolism of drug amines by amine oxidases such as SSAOs and PAOs in humans. In contrast, monooxygenases (CYP isoenzymes, and to a lesser extent, FMOs) have been extensively investigated in terms of their involvement in xenobiotic metabolism. It is possible that the contribution of AOs to the overall metabolism of xenobiotic amines in humans has been underestimated, or erroneously estimated, as most investigations of drug metabolism have been performed using in vitro test systems optimized for CYP activity, such as liver microsomes, and most investigations of drug metabolism in vivo in humans have identified only the final, stable metabolites.

Induction of endogenous pathways by antiepileptics and clinical implications.

The aim of this study was to review modifications of the endogenous pathways (e.g. enzyme elevations, normal body constituent depletion or higher formation/excretion of endogenous metabolites) which could be ascribed to enzyme induction by antiepileptic drugs (AEDs). Information on older (e.g. phenobarbital, phenytoin and carbamazepine) and newer drugs (where information is available) is discussed together with clinical implications. The enzymes involved in the endogenous pathways and induced by the AEDs will not be limited to the hepatic microsomal enzymes; extrahepatic enzymes and/or enzymes present in other subcellular fractions will also be discussed, if pertinent. The induction of endogenous pathways by AEDs has been taken into account in the past, but much less emphasis has been given compared with the extensive literature on induction by AEDs of the metabolism of concomitantly administered drugs, either of the same or of different classes. Not all of the endogenous pathways examined and induced by AEDs appear to result in serious clinical consequences (e.g. induction of hepatic ALP, increased excretion of d-glucaric acid or of 6 beta-hydroxycortisol). In some cases, induction of some pathways (e.g. increase of high-density lipoprotein cholesterol or of conjugated bilirubin) might even be a beneficial side-effect, however enzyme induction is considered rather a detrimental aspect for an AED, as induction is generally a broad and a non-specific phenomenon. The new AEDs have generally less induction potential than the older agents. Yet some (felbamate, topiramate, oxcarbazepine and lamotrigine) have the potential for inducing enzymes, whereas others (levetiracetam, gabapentin and vigabatrin) appear to be completely devoid of enzyme inducing characteristics, at least as far as the enzymes investigated are concerned.

Evaluation of pharmacokinetic interaction between cetirizine and ritonavir, an HIV-1 protease inhibitor, in healthy male volunteers.

BACKGROUND: Serious adverse effects have been observed with some non-sedative H1-antihistamines (terfenadine and astemizole) when they were associated with drugs known to inhibit their metabolism. However, this is not a class effect, and this interaction should be considered on a case-by-case basis. The aim of this study was to evaluate the potential of pharmacokinetic interaction between cetirizine and ritonavir, the most potent cytochrome P450 (CYP) inhibitor. METHODS: An open-label, single-center, one-sequence crossover pharmacokinetic study was conducted in three running periods: cetirizine (CTZ) alone, ritonavir (RTV) alone and then CTZ plus RTV. For each period, steady-state pharmacokinetics were obtained. RTV and CTZ plasma concentrations were determined using validated liquid chromatography methods. The statistical method was based on a 90% confidence interval (CI) for the ratio of population geometric means (combination/drug alone) for each drug and for each parameter [area under the plasma concentration versus time curve (AUC(0-tau,ss)), value of maximum plasma concentration (C(max,ss))] and compared to bioequivalence ranges 80-125% and 70-143% for AUC(0-tau,ss) and C(max,ss), respectively. RESULTS: Among the 17 male subjects enrolled (26.4 +/- 8.6 years), 16 completed the study (1 withdrawal after the first period). The RTV pharmacokinetic parameter values were not affected by CTZ co-treatment. With RTV, a 42% increase in the CTZ AUC(0-tau,ss) (3406 versus 4840 microgh/l, 90% CI of 128-158%), a 53% increase in the CTZ elimination half-life (7.8 h versus 11.9 h, P = 0.001), a slight increase (15%) in the CTZ apparent volume of distribution (V(d,ss)/f) (34.7 l versus 39.8 l, P = 0.035), a 29% decrease in the CTZ apparent total body clearance (49.9 ml/min versus 35.3 ml/min, P < 0.001) and bioequivalent C(max,ss) (374 microg/l versus 408 microg/l) were observed. No serious drug related adverse effects were notified. CONCLUSIONS: CTZ does not significantly affect the pharmacokinetic parameters of RTV, and the association does not, thus, require a modification of the dosage of the protease inhibitor. The increased extent of exposure to CTZ in healthy subjects, in the presence of RTV administered at high doses, remained in the same range as previously observed in the elderly or in mildly renally impaired subjects.

Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations.

In children, the therapeutic benefits and potential risks associated with drug treatment may be different from those in adults and will depend on the exposure, receptor sensitivity and relationship between effect and exposure. In this paper, key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the paediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, secretion and activity of bile and pancreatic fluid, bacterial colonisation and transporters, such as P-glycoprotein (P-gp), are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the paediatric population and adults are organ size, membrane permeability, plasma protein concentration and characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and transporters such as P-gp, which is present not only in the gut, but also in liver, kidney, brain and other tissues. As far as drug metabolism is concerned, important differences have been found in the paediatric population compared with adults both for phase I enzymes (oxidative [e.g., cytochrome P450 (CYP)1A2, and CYP3A7 versus -3A4], reductive and hydrolytic enzymes) and phase II enzymes (e.g., N-methyltransferases and glucuronosyltransferases). Generally, the major enzyme differences observed in comparison with the adult age are in newborn infants, although for some enzymes (e.g., glucuronosyltransferases and other phase II enzymes) important differences still exist between infants and toddlers and adults. Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the paediatric population compared with adults are glomerular filtration and tubular secretion. The ranking of the key factors varies according to the chemical structure and physicochemical properties of the drug examined, as well as to the characteristics of its formulation. It would be important to generate additional information on the developmental aspects of renal P-gp and of other renal transporters, as has been done and is still being done with the different -isozymes involved in drug metabolism.

Drug metabolism and disposition in children.

Key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the pediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, bacterial colonization and probably P-glycoprotein are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein concentration and plasma protein characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and probably P-glycoprotein, mainly that present in the gut, liver and brain. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I enzymes [oxidative (e.g. cytochrome CYP3A7 vs. CYP3A4 and CYP1A2), reductive and hydrolytic enzymes] and phase II enzymes (e.g. N-methyltransferases and glucuronosyltransferases). Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the pediatric population compared with adults are glomerular filtration and tubular secretion. It would be important to generate information on the developmental aspects of renal P-glycoprotein and of other renal transporters as done and still being done with the different isozymes involved in drug metabolism.

Absorption and disposition of levocetirizine, the eutomer of cetirizine, administered alone or as cetirizine to healthy volunteers.

The primary objective of the present study was to compare the absorption and disposition of levocetirizine, the eutomer of cetirizine, when administered alone (10 mg) or in presence of the distomer. An additional objective was also to investigate the configurational stability of levocetirizine in vivo in humans. The study was performed in a randomized, two-way cross-over, single-dose design with a wash-out phase of 7 days between the two periods. A total of 12 healthy male and 12 healthy female volunteers were included in the study. Bioequivalence can be concluded from the analysis of the pharmacokinetic parameters of levocetirizine when administered alone or as the racemate cetirizine. No chiral inversion occurs in humans when levocetirizine is administered, i.e. there is no formation of the distomer. When comparing the pharmacokinetic characteristics of levocetirizine and the distomer, the apparent volume of distribution of the eutomer is significantly smaller than that of the distomer (0.41 and 0.60 L/kg, respectively). For an H1-antagonist a small distribution volume can be considered as a positive aspect, both in terms of efficacy and safety. Moreover the non-renal clearance of levocetirizine is also significantly lower than that of the distomer (9.70 and 28.70 mL/min, respectively), which constitutes an additional positive aspect particularly as far as metabolism-based drug interactions are concerned. The information collected in the present study on the pharmacokinetics of levocetirizine and the distomer provide additional reasons for eliminating the distomer and developing levocetirizine as an improvement on cetirizine.

N-methyl(R)salsolinol and a neutral N-methyltransferase as pathogenic factors in Parkinson's disease.

The pathogenesis of Parkinson's disease is still an enigma. As an endogenous MPTP-like neurotoxin, N-methyl(R)salsolinol was proved to induce parkinsonism in rats and apoptosis in dopaminergic neurons. It is synthesized in the human brain by two enzymes; an (R)salsolinol synthase and an N-methyltransferase, and accumulates in the nigro-striatum in human brains. The activity of a neutral N-methyltransferase in the striatum was found to determine the level of MPP+-like 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion, an oxidation product of N-methyl(R)salsolinol in the substantia nigra. The activity of this N-methyltransferase was found to increase significantly in lymphocytes prepared from parkinsonian patients. In cerebrospinal fluid from untreated parkinsonian patients, N-methyl(R)-salsolinol increases significantly. These results suggest that N-methyl(R)salsolinol and a neutral N-methyltransferase may be endogenous factors in the pathogenesis of Parkinson's disease.

Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration.

1. Z-7760 (S(-)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. 3H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mg and 400 microCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total 3H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma 3H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma 3H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routes of administration. 3. The bile duct-cannulated rat was given 3H-Z-7760 p.o. (0.4 mg and 40 microCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with 3H-Z-7760 (0.4 mg and 400 microCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% 3H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100 mg/kg, 40 microCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces systemic blood concentrations after oral administration.

Association of cytochrome P450 induction with oxidative stress in vivo as evidenced by 3-hydroxylation of salicylate.

1. Previous studies have shown that formation of 2,3-dihydroxybenzoate (2,3-DHB) from salicylate in vivo is a sensitive and specific marker of *OH radical generation, since 2,3-DHB is formed exclusively by *OH radicals, whereas both *OH radicals and cytochrome P450 (CYP) contribute to the production of 2,5-DHB. In the present study the salicylate-hydroxylation assay was used to examine whether CYP induction by the administration of dexamethasone, phenobarbital or beta-naphthoflavone to the male rat led to oxidative stress in vivo. 2. Dexamethasone was used under conditions that induced an approximately 50-fold induction of CYP P4503A expression in liver microsomal protein. Treatment with dexamethasone caused a 17.2-fold increase in 2,3-DHB plasma concentration compared with control animals. An increase in total hydroxylated salicylate (2,3-DHB plus 2,5-DHB) of 133.5 micromol/l plasma was produced, of which--assuming that the attack by *OH in position 3 or 5 of salicylate occurs at a similar rate--10.9 micromol/l were due to *OH radical attack and 122.6 micromol/l due to metabolism by CYP. 3. Phenobarbital led to a 4.7-fold increase in 2,3-DHB plasma concentration under conditions that induced CYP P4502B and 3A. An increase in total hydroxylated salicylate of 34.3 micromol/l plasma was observed, 2.0 micromol/l due to *OH radical attack and 32.3 micromol/l due to metabolism by cytochrome P450. 4. In contrast to dexamethasone and phenobarbital, beta-naphthoflavone did not cause a significant increase in 2,3-DHB plasma concentrations. 5. SKF 525A, a mixed-function oxidase inhibitor, caused a significant reduction of mean 2,5-DHB plasma concentration by 35% (p < 0.001), whereas 2,3-DHB was not significantly reduced, indicating that in contrast to the situation after induction by dexamethasone or phenobarbital, *OH radical generation by constitutive CYP contributes only to a minor degree to total in vivo *OH radical generation. 6. This study shows for the first time, to the authors' knowledge, that induction of some (but not all) P450s is associated with the production of hydroxyl radicals in vivo.

Design of in vitro studies to predict in vivo inhibitory drug-drug interactions.

In vitro studies offer great potential for achieving helpful information for predicting clinical interactions between concomitantly administered drugs. Since the metabolism of drugs usually involves several pathways, the enzyme or CYP isozymes known to contribute to the metabolism of the majority of therapeutic drugs should be preferentially studied. To make corrective intervention in the stages of drug discovery and to improve the process of drug development, an early investigation of potential inhibitory drug-drug interactions is required.

Monoamine oxidases and related amine oxidases as phase I enzymes in the metabolism of xenobiotics.

To date most of the interest in oxidative metabolism of xenobiotics has been devoted to the role of the microsomal cytochrome P-450 system and to establish the basis for classifying and naming P450 enzymes. The contribution of amine oxidases to the metabolism of xenobiotics has been largely neglected, with the exception of the contribution of monoamine oxidases (MAOs) to the metabolism of exogenous tyramine and the studies of the "cheese effect" produced as the result of ingestion of large amounts of tyramine-containing foods under particular conditions. A review of the involvement of the mitochondrial MAOs in drug metabolism was published in 1988. Since that time, considerable additional evidence has appeared in the literature to support the contribution of MAOs to drug metabolism. In addition, the involvement of other amine oxidases in the metabolism of foreign compounds has been established. A second review on the contribution of amine oxidases to the metabolism of xenobiotics was therefore published in 1994. On an arbitrary basis, the heterogeneous class of amine oxidases can be divided into two types according to their prosthetic group: the flavineadenine dinucleotide (FAD)-dependent amine oxidases (Monoamine Oxidase and Polyamine Oxidase) and the amine oxidases not containing FAD (Semicarbazide-sensitive amine oxidases). In this overview, the contributions of these two types in xenobiotic metabolism are considered separately.

The oxidation of dopamine and epinine by the two forms of monoamine oxidase from rat liver.

Information on the "in vitro" oxidation of epinine by monoamine oxidase (MAO) compared to dopamine is very poor. The aim of this work was to study the oxidative deamination of epinine and dopamine by rat liver MAO-A and MAO-B. The contributions of MAO-A and B to the metabolism of dopamine (55% and 45%, respectively) and epinine (70% and 30%, respectively) were similar. The results of this study show that epinine is a substrate for both forms of MAO in rat liver, although the contribution of MAO A to the deamination of this secondary amine appears to be slightly more important than that of MAO B.

Clinical and pharmacokinetic evaluation of L-dopa and cabergoline cotreatment in Parkinson's disease.

Previous investigations on the mutual pharmacokinetic influence of L-dopa and dopamine agonists in Parkinson's disease (PD) have shown controversial results. Two studies of the possible clinical and pharmacokinetic interaction between L-dopa and cabergoline were performed in 10 patients with de novo PD and 12 patients with fluctuating PD. In the first study (de novo patients), cabergoline was administered at increasing dosages until the maximum dosage of 2 mg/day once a day for 8 weeks; subsequently L-dopa (250 mg/day) was added. Blood levels of cabergoline were assayed in two different days, before starting L-dopa, and 1 week thereafter. In the second 8-week study (fluctuating patients), cabergoline was added to the current L-dopa therapy (maximum dosage 4 mg/day once a day). Blood levels of L-dopa were measured in two different days, before cabergoline was added, and at the end of the study. In both studies motor performance was evaluated by means of the Unified Parkinson's Disease Rating Scale (motor examination) and the Clinical Global Impression Scale; on-off diaries of daily motor condition also were filled by fluctuating patients. In patients with de novo PD, cabergoline pharmacokinetic parameters were unmodified by the adjunct of L-dopa, except that the time to reach the peak concentration (Tmax) significantly increased after L-dopa. In patients with fluctuating PD, no modification of L-dopa pharmacokinetics was observed before and after cabergoline coadministration. Clinical evaluations confirmed that cabergoline is effective in the treatment of advanced PD as well as in the management of de novo patients.

A study of the pharmacokinetics and tolerability of ritipenem acoxil in healthy volunteers following multiple oral dosing.

The pharmacokinetics of ritipenem acoxil, the oral prodrug of the antibiotic ritipenem, were studied in volunteers after single and repeated dosing (500 mg, three times daily for 10 days). Concentrations of ritipenem and open beta-lactam ring metabolites were measured using HPLC/UV. Ritipenem did not accumulate significantly in plasma, owing to its half-life of about 0.7 h; the area under the curve for 0-8 h was on average about 10 mg x h/L. Plasma pharmacokinetics of ritipenem and metabolites were time-independent. A decrease of ritipenem renal clearance (87 versus 132 mL/min) and a slight increase in the amount of metabolites excreted in urine were observed following repeated dosing.

Preliminary pharmacokinetic study of ibuprofen enantiomers after administration of a new oral formulation (ibuprofen arginine) to healthy male volunteers.

The pharmacokinetics of ibuprofen enantiomers were investigated in a crossover study in which seven healthy male volunteers received single oral doses of 800 mg racemic ibuprofen as a soluble granular formulation (sachet) containing L-arginine (designated trade name: Spedifen), 400 mg (-)R-ibuprofen arginine or 400 mg (+)S-ibuprofen arginine. Plasma levels of both enantiomers were monitored up to 480 minutes after drug intake using an enantioselective analytical method (HPLC with ultraviolet detection) with a quantitation limit of 0.25 mg/l. Substantial inter-subject variability in the evaluated pharmacokinetic parameters was observed in the present study. After (+)S-ibuprofen arginine, the following mean pharmacokinetic parameters +/-SD were calculated for (+)S-ibuprofen: tmax 28.6 +/- 28.4 min; Cmax 36.2 +/- 7.7 mg/l; AUC 86.4 +/- 14.9 mg.h/l; t1/2 105.2 +/- 20.4 min. After (-)R-ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S-ibuprofen and (-)R-ibuprofen, respectively: tmax 90.0 +/- 17.3 and 50.5 +/- 20.5 min; Cmax 9.7 +/- 3.0 and 35.3 +/- 5.0 mg/l; AUC 47.0 +/- 17.2 and 104.7 +/- 27.7 mg.h/l; t1/2 148.1 +/- 63.6 and 97.7 +/- 23.3 min. After racemic ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S- and (-)R-ibuprofen, respectively: tmax 30.7 +/- 29.1 and 22.9 +/- 29.8 min; Cmax 29.9 +/- 5.6 and 25.6 +/- 4.4 mg/l; AUC 105.1 +/- 23.0 and 65.3 +/- 15.0 mg.h/l; t1/2 136.6 +/- 20.7 and 128.6 +/- 45.0 min. Tmax values of S(+)- and (-)R-ibuprofen after a single dose of 400 mg of each enantiomer did not differ significantly from the corresponding parameters obtained after a single dose of 800 mg of racemic ibuprofen arginine, indicating that the absorption rate of (-)R- and (+)S-ibuprofen is not different when the two enantiomers are administered alone or as a racemic compound. An average of 49.3 +/- 9.0% of a dose of the (-)R-ibuprofen arginine was bioinverted into its antipode during the study period (480 minutes post-dosing). The percent bioinversion during the first 30 minutes after (-)R-ibuprofen arginine intake averaged 8.1 +/- 3.9%. The mean AUC of (+)S-ibuprofen calculated after 800 mg racemic ibuprofen arginine (105.1 +/- 23.0 mg.h/l) was lower than the mean AUC value obtained by summing the AUCs of (+)S-ibuprofen after administration of 400 mg (+)S-ibuprofen arginine and 400 mg (-)R-ibuprofen arginine (133.4 +/- 26.6 mg.h/l). In conclusion, the administration of Spedifen resulted in very rapid absorption of the (+)S-isomer (eutomer) with tmax values much lower than those observed for this isomer when conventional oral solid formulations such as capsules or tablets of racemic ibuprofen are administered. This characteristic is particularly favourable in those conditions in which a very rapid analgesic effect is required.

Pharmacokinetics of reboxetine enantiomers in the dog.

Reboxetine, (RS)-2-[(RS)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. The pharmacokinetics of reboxetine enantiomers were determined in a crossover study in three male beagle dogs. Each animal received the following oral treatments, separated by 1-week washout period: 10 mg/kg reboxetine, 5 mg/kg (R,R)- and 5 mg/kg (S,S)-. Plasma and urinary levels of the reboxetine enantiomers were monitored up to 48 h post-dosing using an enantiospecific HPLC method with fluorimetric detection (LOQ: 1.1 ng/ml in plasma and 5 ng/ml in urine for each enantiomer). After reboxetine administration mean tmax was about 1 h for both enantiomers. Cmax and AUC were about 1.5 times higher for the (R,R)- than for the (S,S)-enantiomer, mean values +/- SD being 704 +/- 330 and 427 +/- 175 ng/ml for Cmax and 2,876 +/- 1,354 and 1,998 +/- 848 ng.h/ml for AUC, respectively. No differences between the (R,R)- and (S,S)-enantiomers were observed in t1/2 (3.9 h). Total recovery of the two enantiomers in urine was similar, the Ae (0-48 h) being 1.3 +/- 0.7 and 1.1 +/- 0.7% of the enantiomer dose for the (R,R)- and the (S,S)-enantiomers, respectively. No marked differences in the main plasma pharmacokinetic parameters were found for either enantiomer on administration of the single enantiomers or reboxetine. No chiral inversion was observed after administration of the separate enantiomers, as already observed in humans.