Metabolism and excretion of asenapine in healthy male subjects.

The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [(14)C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was ∼90%, with ∼50% appearing in urine and ∼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.

Pharmacokinetic parameters of tibolone and metabolites in plasma, urine, feces, and bile from ovariectomized cynomolgus monkeys after a single dose or multiple doses of tibolone.

Levels of nonsulfated and sulfated tibolone metabolites were determined in plasma, urine, and feces from six ovariectomized, mature female cynomolgus monkeys after a single dose and multiple p.o. doses (including bile) of tibolone using validated gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry assays. In plasma, the predominant nonsulfated metabolite after single and multiple dosing was the estrogenic 3alpha-hydroxytibolone; levels of the estrogenic 3beta-hydroxytibolone were 10-fold lower and of progestagenic/androgenic Delta(4)-tibolone, 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone; levels of 3betaS,17betaS-tibolone were about 2-fold lower, and monosulfated 3-hydroxymetabolites were about 10-fold lower. After multiple doses, areas under the curve of nonsulfated metabolites were lower (2-fold), and those of sulfated metabolites were 25% higher. In plasma, >95% metabolites were disulfated. In urine, levels of all the metabolites after single and multiple doses were low. After a single dose, high levels of 3beta-hydroxytibolone and the 3-monosulfated metabolites (3betaS,17betaOH-tibolone and 3alphaS,17betaOH-tibolone) were found in feces. After multiple dosing, 3alpha-hydroxytibolone increased, and the ratio of 3alpha/3beta-hydroxytibolone became about 1. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone. Levels of all the metabolites in feces were higher after multiple doses than after a single dose. Levels of nonsulfated and 3-monosulfated metabolites were higher in feces than in plasma. Bile contained very high metabolite levels, except monosulfates. This may contribute to the metabolite content of the feces after multiple doses. 3beta-Hydroxytibolone and 3alphaS,17betaS-tibolone predominated. In conclusion, tibolone had different metabolite patterns in plasma, urine, feces, and bile in monkeys. The bile contributed to the metabolite pattern in feces after multiple doses. The major excretion route was in feces.

Selective tissue distribution of tibolone metabolites in mature ovariectomized female cynomolgus monkeys after multiple doses of tibolone.

Tibolone is a selective tissue estrogenic activity regulator (STEAR). In postmenopausal women, it acts as an estrogen on brain, vagina, and bone, but not on endometrium and breast. Despite ample supporting in vitro data for tissue-selective actions, confirmative tissue levels of tibolone metabolites are not available. Therefore, we analyzed tibolone and metabolites in plasma and tissues from six ovariectomized cynomolgus monkeys that received tibolone (0.5 mg/kg/day by gavage) for 36 days and were necropsied at 1, 1.25, 2.25, 4, 6, and 24 h after the final dose. The plasma and tissue levels of active, nonsulfated (tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, and Delta(4)-tibolone), monosulfated (3alpha-sulfate,17beta-hydroxytibolone and 3beta-sulfate,17beta-hydroxytibolone), and disulfated (3alpha,17beta-disulfated-tibolone and 3beta,17betaS-disulfated-tibolone) metabolites were measured by validated gas chromatography with mass spectrometry and liquid chromatography with tandem mass spectrometry. Detection limits were 0.1 to 0.5 ng/ml (plasma) and 0.5 to 2 ng/g (tissues). In brain tissues, estrogenic 3alpha-hydroxytibolone was predominant with 3 to 8 times higher levels than in plasma; levels of sulfated metabolites were low. In vaginal tissues, major nonsulfated metabolites were 3alpha-hydroxytibolone and the androgenic/progestagenic Delta(4)-tibolone; disulfated metabolites were predominant. Remarkably high levels of monosulfated metabolites were found in the proximal vagina. In endometrium, myometrium, and mammary glands, levels of 3-hydroxymetabolites were low and those of sulfated metabolites were high (about 98% disulfated). Delta(4)-Tibolone/3-hydroxytibolone ratios were 2 to 3 in endometrium, about equal in breast and proximal vagina, and 0.1 in plasma and brain. It is concluded that tibolone metabolites show a unique tissue-specific distribution pattern explaining the tissue effects in monkeys and the clinical effects in postmenopausal women.

The in vivo metabolism of tibolone in animal species.

The in vivo tissue distribution and metabolism of tibolone was studied in different animals to further investigate the compound's tissue-specificity. Tibolone's metabolism was studied in vivo in rats and rabbits by administration of [16-3H]-tibolone and the metabolic pattern was determined in urine and faeces after oral administration to female rats and dogs. The main excretory pathway was found to be excretion in the faeces. Important phase-I metabolic routes were the reduction of the 3-keto to the 3a- or 3beta-hydroxy functions with a preference for 3alpha-OH in rats and for 3beta-OH in dogs. To a lesser extent, hydroxylation reactions at C2 and C7, and a shift of the delta5(10)-double bond to a delta4(5)-position also occurred. The main phase-II metabolic route was sulphate conjugation of the hydroxyl groups at C3 and C17. Since the oxidation reactions form only a minor part of the metabolism of tibolone, it is concluded that the cytochrome P450 enzymes do not play an important role in tibolone's metabolism. For both phases, quantitative differences were found between the species. In human similar metabolites are found. Profiling of the target organs in female rats and rabbits showed a tissue-specific distribution of metabolites. The majority of the metabolites existed as sulphate conjugates and no glucuronidated conjugates were observed. The same metabolites were found in both the circulation and the tissues. However, different tissues had quantitatively different metabolic profiles.

The in vivo human metabolism of tibolone.

In vivo metabolism of tibolone was studied in three healthy postmenopausal volunteers after daily oral administration of 2.5 mg of tibolone for 5 days and a single dose of 2.5 mg approximately equal 555 kBq of [(14)C]tibolone on day 6. The 0- to 192-h recovery of radioactivity in urine and feces was 31.2 +/- 10.5 and 53.7 +/- 5.1%, respectively. Total 0- to 192-h recovery ranged from 78.5 to 94.2% of the dose and averaged 84.9%. Metabolites were putatively identified using high-pressure liquid chromatography in plasma, urine, and feces. The most important phase I metabolic reactions were reduction of the 3-keto group to 3alpha- and 3beta-hydroxy metabolites, a shift of the Delta(5(10))-double bond to a Delta(4(5))-double bond, a reduction of the Delta(4(5))-double bond to 5alpha,10-dihydro or 5beta,10-dihydro metabolites, and hydroxylation at C2 and C7. The most important phase II metabolic reaction is sulfation of the C17 hydroxy group of tibolone and sulfation of the C3 hydroxy groups. In the circulation, over 75% of tibolone and its metabolites are present in the sulfated form. Local metabolism and local sulfatases may contribute to the tissue-specific activity. Using human microsomes, tibolone, 3alpha-hydroxy tibolone, 3beta-hydroxy tibolone, and Delta(4)-tibolone appeared to be at least 50-fold less potent inhibitors of CYP1A2, CYP2C9, CYP2E1, and CYP3A4 compared with enzyme-selective inhibitors. Tibolone and its metabolites, therefore, are not likely to play a clinically significant role at the level of these cytochrome P450 enzymes with regard to the metabolism of coadministered drugs.

Clinical pharmacokinetics of mirtazapine.

Mirtazapine is the first noradrenergic and specific serotonergic antidepressant ('NaSSA'). It is rapidly and well absorbed from the gastrointestinal tract after single and multiple oral administration, and peak plasma concentrations are reached within 2 hours. Mirtazapine binds to plasma proteins (85%) in a nonspecific and reversible way. The absolute bioavailability is approximately 50%, mainly because of gut wall and hepatic first-pass metabolism. Mirtazapine shows linear pharmacokinetics over a dose range of 15 to 80mg. The presence of food has a minor effect on the rate, but does not affect the extent, of absorption. The pharmacokinetics of mirtazapine are dependent on gender and age: females and the elderly show higher plasma concentrations than males and young adults. The elimination half-life of mirtazapine ranges from 20 to 40 hours, which is in agreement with the time to reach steady state (4 to 6 days). Total body clearance as determined from intravenous administration to young males amounts to 31 L/h. Liver and moderate renal impairment cause an approximately 30% decrease in oral mirtazapine clearance; severe renal impairment causes a 50% decrease in clearance. There were no clinically or statistically significant differences between poor (PM) and extensive (EM) metabolisers of debrisoquine [a cytochrome P450 (CYP) 2D6 substrate] with regard to the pharmacokinetics of the racemate. The pharmacokinetics of mirtazapine appears to be enantioselective, resulting in higher plasma concentrations and longer half-life of the (R)-(-)-enantiomer (18.0 +/-2.5h) compared with that of the (S)-(+)-enantiomer (9.9+/-3. lh). Genetic CYP2D6 polymorphism has different effects on the enantiomers. For the (R)-(-)-enantiomer there are no differences between EM and PM for any of the kinetic parameters; for (S)-(+)-mirtazapine the area under the concentration-time curve (AUC) is 79% larger in PM than in EM, and a corresponding longer half-life was found. Approximately 100% of the orally administered dose is excreted via urine and faeces within 4 days. Biotransformation is mainly mediated by the CYP2D6 and CYP3A4 isoenzymes. Inhibitors of these isoenzymes, such as paroxetine and fluoxetine, cause modestly increased mirtazapine plasma concentrations (17 and 32%, respectively) without leading to clinically relevant consequences. Enzyme induction by carbamazepine causes a considerable decrease (60%) in mirtazapine plasma concentrations. Mirtazapine has little inhibitory effects on CYP isoenzymes and, therefore, the pharmacokinetics of coadministered drugs are hardly affected by mirtazapine. Although no concentration-effect relationship could be established, it was found that with therapeutic dosages of mirtazapine (15 to 45 mg/day), plasma concentrations range on average from 5 to 100 microg/L.

Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs.

PURPOSE: To study oral absorption and brain penetration as a function of polar molecular surface area. METHODS: Measured brain penetration data of 45 drug molecules were investigated. The dynamic polar surface areas were calculated and correlated with the brain penetration data. Also the static polar surface areas of 776 orally administered CNS drugs that have reached at least Phase II efficacy studies were calculated. The same was done for a series of 1590 orally administered non-CNS drugs that have reached at least Phase II efficacy studies. RESULTS: A linear relationship between brain penetration and dynamic polar surface area (A2) was found (n = 45, R = 0.917, F1,43 = 229). Brain penetration decreases with increasing polar surface area. A clear difference between the distribution of the polar surface area of the 776 CNS and 1590 non-CNS drugs was found. It was deduced that orally active drugs that are transported passively by the transcellular route should not exceed a polar surface area of about 120 A2. They can be tailored to brain penetration by decreasing the polar surface to <60-70 A2. This conclusion is supported by the inverse linear relationship between experimental brain penetration data and the dynamic polar surface area of 45 drug molecules. CONCLUSIONS: The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route. This property should be considered in the early phase of drug screening.

Pharmacokinetics and biotransformation of mirtazapine in human volunteers.

This paper investigated the pharmacokinetics and biotransformation of mirtazapine in healthy human volunteers. The results showed that the area under the plasma drug concentration-time curve (AUC) of mirtazapine in human plasma appeared to be three times higher than the AUC of demethylmirtazapine. As mirtazapine is marketed as a racemic mixture and both enantiomers possess pharmacological properties essential for the overall activity of the racemate, the pharmacokinetics of mirtazapine were examined and appeared to be enantioselective. The R(-)-enantiomer showed the longest elimination half-life from plasma. This was ascribed to the preferred formation of a quaternary ammonium glucuronide of the R(-)-enantiomer. This glucuronide may be deconjugated, leading to a further circulation of the parent compound, thus causing a prolongation in the elimination half-life. The S(+)-enantiomer was preferentially metabolised into an 8-hydroxy glucuronide. Other metabolic transformation pathways found for mirtazapine were demethylation and N-oxidation. Mirtazapine was extensively metabolised and almost completely excreted in the urine (over 80%) and faeces within a few days after oral administration.

A comparison of the physicochemical and biological properties of mirtazapine and mianserin.

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated. Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pKa value, is slightly but significantly lower than that of mianserin. The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the alpha 1-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.

The clinical relevance of preclinical data: mirtazapine, a model compound.

This paper discusses how in vitro and preclinical in vivo studies might be of help for the interpretation and prediction of possible clinically relevant effects. The examples given refer to the data obtained with mirtazapine, a novel antidepressant with a dual mechanism of action, which can be best summarized as a noradrenergic and specific serotonergic antidepressant. Preclinical data on mirtazapine have shown that (i) its binding to plasma proteins is relatively low and non-specific; (ii) the contribution of its metabolites to the pharmacologic effect is negligible; (iii) it possesses high bioavailability, resulting in a low variance between individuals; (iv) it has no inducing or inhibiting effects on hepatic P450 enzymes; (v) it has a very low potential for clinically relevant pharmacokinetic interactions with other drugs; and (vi) its disposition is independent of polymorphic CYP2D6 activity. The available preclinical data on mirtazapine could be used to advise clinicians and to guide clinical practice.

Antiarrhythmic and electrophysiological effects in-vivo of the major metabolite of Org 7797 found in canine and rodent liver homogenate preparations.

Org 20781, the major metabolite of Org 7797 found in in-vitro experiments was examined for antiarrhythmic and electrophysiological effects in-vivo. Org 20781 (0.5-2.0mg kg-1, i.v.) inhibited the development of early ischaemia-induced arrhythmias in rats, suppressed spontaneous ventricular tachycardia (VT) in conscious dogs with 24-h old infarcts, and prevented electrical induction of VT in dogs with 5-6 day old infarcts, actions associated with slowing of conduction at all levels of the myocardium. Cardiac refractory periods were only modestly prolonged whilst repolarization was unchanged. Peak plasma levels of the parent compound (infused to total doses of 2-4 mg kg-1) associated with suppression of late arrhythmias were 6-18 microM, whilst the mean plasma elimination half-life (in normal dogs) was 107 min. It was concluded that the major metabolite has a similar antiarrhythmic and electrophysiological profile to the parent compound, is at least half as potent and may contribute to the therapeutic effects of Org 7797 administration.

Metabolism of three pharmacologically active drugs in isolated human and rat hepatocytes: analysis of interspecies variability and comparison with metabolism in vivo.

1. The metabolism of the three drugs (Org GB 94, Org 3770 and Org OD 14) was studied in isolated human and rat hepatocytes. The metabolic profiles in rat and human hepatocytes were compared with the available in vivo data in both species. 2. All three drugs were metabolized extensively under the conditions used, both in human and rat hepatocytes, showing both extensive phase I and II metabolism. 3. During 3-h incubation with rat hepatocytes the three compounds were metabolized completely, whereas incubation with human hepatocytes only resulted in partial metabolism, amounting for 58% (Org GB 94), 36% (Org 3770) and 94% (Org OD 14) of the dose. In addition, rat hepatocytes excreted relatively more of the formed metabolites than human hepatocytes. 4. For both species, the metabolites formed in the isolated cells were quite similar to those found in vivo. With respect to Org GB 94 and Org 3770, metabolites were detected in man in vivo and in isolated human hepatocytes that were not found in any of the animal species studied previously. 5. The reflection of interspecies differences in isolated hepatocytes, with respect to both metabolite profiles and human-specific metabolites, renders isolated human hepatocytes a very valuable tool during preclinical drug development.

Enantiomeric aspects of the metabolism of mianserin in rats.

After separate administration of mianserin (CAS 24219-97-4) enantiomers to rats, the hydroxy-metabolites of S-mianserin were excreted mainly as conjugates whereas the amount of free phenolic metabolites was greater after administration of the R-enantiomer. The sulphate-conjugate of 8-hydroxy-mianserin was stereoselectively found in faeces only after administration of S-mianserin. Based on in vitro experiments with sulphatase, the stability of this conjugate towards enzymic hydrolysis appears a likely explanation. In vitro experiments with liver homogenates of rats revealed little enantioselectivity with respect to oxidative metabolism. After prior enzyme induction with phenobarbital, however, enantioselectivity with regard to N-oxidation was found. The 3-oxo-mianserin metabolite, found in vitro, is most likely the product of a rearrangement of mianserin-N-oxide. N-formyl-demethyl-mianserin, identified in vitro, is considered to be an artefact.

Antiarrhythmic, electrophysiological and haemodynamic effects of prolonged oral dosing with Org 7797 in the anaesthetized rat.

The antiarrhythmic, electrophysiological and haemodynamic effects of chronic oral administration of Org 7797 ((16 alpha,17 beta)-17-methylamino-oestra-1,3,5(10)-triene-3, 16-diol-(Z)-2-butonedioate) were studied in rats. During dosing (10 mg kg-1 twice a day for 10 days) no effects on the electrocardiogram, monitored in conscious animals, were observed despite modest reductions (15-18%) in the maximum rate of depolarization of papillary muscle excised 1 or 6 h after completion of the dosing regime. Following anaesthesia, Org 7797 reduced the severity of arrhythmias induced by coronary artery occlusion and prevented the accompanying decrease in the ventricular fibrillation threshold (VFT) at 1 h after completion of dosing. By 6 h the effect on VFT had waned but protection against ischaemia-induced arrhythmias was retained despite a substantial decrease in Org 7797 plasma levels. Drug treatment did not modify arterial blood pressure, heart rate or stroke volume. We conclude that Org 7797 given chronically via the oral route exerts antiarrhythmic actions which may, at least in part, be due to sodium-channel block. In addition, our results suggest the presence of an active metabolite. The protective effects of Org 7797 were seen in the absence of electrocardiographic or haemodynamic changes suggesting that multiple oral doses of Org 7797 do not compromise normal cardiac function.

Biotransformation of mianserin in laboratory animals and man.

1. The biotransformation and excretion of the antidepressant mianserin were studied after oral administration of the labelled drug to rats, mice, rabbits, guinea pigs and humans. Mianserin was well absorbed and almost completely metabolized in all five species. 2. Major metabolic pathways of mianserin were p-oxidation of the N-substituted aromatic ring followed by conjugation, and oxidation and demethylation of the N-methyl moiety, followed by conjugation. Direct conjugation of the N-methyl moiety was observed as a metabolic pathway specific for man. 3. Conjugated metabolites were isolated by h.p.l.c. and identified by 1H-n.m.r. and FAB spectrometry. Novel metabolites such as an N-O-glucuronide in the guinea pig and an N-sulphonate in rat and guinea pig, were identified using these techniques. A quaternary N-glucuronide was found only in man.

Biotransformation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1-H-dibenz[2,3:6,7]oxepin o [4,5-c]pyrrolidine maleate in rats.

The metabolism of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H-dibenz[2,3:6,7]oxepinol [4,5-c]pyrrolidine maleate (Org 5222) labelled with [3H] or [14C] was investigated in Wistar rats. Metabolites were identified by mass spectrometry, 13C- and 1H-NMR analysis, IR spectroscopy and, wherever possible, by comparison with authentic reference compounds. The metabolites found in plasma, bile, faeces and urine revealed the processes of metabolism in which Org 5222 underwent oxidation to yield an N-oxide existing in two diastereoisomeric forms, or N-demethylation to yield a demethyl metabolite. A novel metabolite was found in bile, viz. a carbamate glucuronide, formed from an intermediate carbamic acid, derived from the addition of CO2 to the demethyl metabolite.

A mass spectrometric approach to the identification of conjugated drug metabolites.

For the identification of intact underivatized drug conjugates, the mass spectrometric technique of choice is fast atom bombardment (FAB); the combined use of both positive and negative ion FAB usually provides information on the molecular mass and nature of conjugates under study, while the number of exchangeable hydrogen atoms can be determined using trideuterated glycerol as the FAB-matrix. Electron impact and desorption chemical ionization spectra can be used to study the aglycone part of the conjugated metabolites. With this approach metabolites conjugated with glucuronic acid, sulphuric acid and amino acids have been identified. The identification was supported by analysis of reference compounds, prepared by chemical synthesis. The examples given are selected from current metabolism studies on drug candidates in development within Organon's research.

2-Chlorobenzylmercapturic acid, a metabolite of the riot control agent 2-chlorobenzylidene malononitrile (CS) in the rat.

Adult male Wistar rats administered i.p. with 2-chlorobenzylidene malononitrile (CS) excreted one mercapturic acid in urine. The amount of mercapturic acid determined gaschromatographically was about 4% of the dose (0.07 mmol/kg, n = 12). The structure of the mercapturic acid methylester was identified by t.l.c. and confirmed by synthesis and mass-spectrography. The acid appeared to be 2-chlorobenzylmercapturic acid [N-acetyl-S-(2-chlorobenzyl)-L-cysteine]. CS and some of its metabolites were also tested in the Ames Salmonella/microsome assay. Both mutagenic and toxic effects were measured with strain TA 100 as the indicator organism. No mutagenic effects were found with any of the tested substances. At dosages of CS, higher than 1,000 micrograms/plate a bacteriotoxicity was revealed.

Concomitant sensitization to hydroquinone and P-methyoxyphenol in the guinea pig; inhibitors in acrylic monomers.

Concomitant sensitization to hydroquinone and p-methoxyphenol occurred in sensitization experiments with acrylic monomers in guinea pigs. No relation between the concentration of the inhibitor in the monomers and the incidence of these concomitant sensitizations could be detected. Concomitant sensitization did not influence the cross reaction pattern of the acrylic monomers. The sensitizing potential of acrylic monomers is not influenced by the inhibitors, but some acrylic monomers seem to interfere with the sensitizing potential of the inhibitors.