Comparison of TiO2 photocatalysis, electrochemically assisted Fenton reaction and direct electrochemistry for simulation of phase I metabolism reactions of drugs.

The feasibility of titanium dioxide (TiO2) photocatalysis, electrochemically assisted Fenton reaction (EC-Fenton) and direct electrochemical oxidation (EC) for simulation of phase I metabolism of drugs was studied by comparing the reaction products of buspirone, promazine, testosterone and 7-ethoxycoumarin with phase I metabolites of the same compounds produced in vitro by human liver microsomes (HLM). Reaction products were analysed by UHPLC-MS. TiO2 photocatalysis simulated the in vitro phase I metabolism in HLM more comprehensively than did EC-Fenton or EC. Even though TiO2 photocatalysis, EC-Fenton and EC do not allow comprehensive prediction of phase I metabolism, all three methods produce several important metabolites without the need for demanding purification steps to remove the biological matrix. Importantly, TiO2 photocatalysis produces aliphatic and aromatic hydroxylation products where direct EC fails. Furthermore, TiO2 photocatalysis is an extremely rapid, simple and inexpensive way to generate oxidation products in a clean matrix and the reaction can be simply initiated and quenched by switching the UV lamp on/off.

Are hERG channel blockers also phospholipidosis inducers?

Both pharmacophore models of the human ether-à-go-go-related gene (hERG) channel blockers and phospholipidosis (PLD) inducers contain a hydrophobic moiety and a hydrophilic motif/positively charged center, so it is interesting to investigate the overlap between the ligand chemical spaces of both targets. We have assayed over 4000 non-redundant drug-like compounds for both their hERG inhibitory activity and PLD inducing potential in a quantitative high throughput screening (qHTS) format. Seventy-seven percent of PLD inducing compounds identified from the screening were also found to be hERG channel blockers, and 96.9% of the dually active compounds were positively charged. Among the 48 compounds that induced PLD without inhibiting hERG channel, 24 compounds (50.0%) carried steroidal structures. According to our results, hERG channel blockers and PLD inducers share a large chemical space. In addition, a positively charged hERG channel blocker will most likely induce PLD, while a steroid PLD inducer is less likely a hERG channel blocker.

Interactions of phenothiazine drugs with bile salts: micellization and binding studies.

An evaluation of the interactions of phenothiazine tranquilizer drugs (promazine hydrochloride; PMZ and promethazine hydrochloride; PMT) with bile salts viz., sodium cholate (NaC) and sodium deoxycholate (NaDC) in aqueous medium, investigated through different physicochemical measurements is presented in this work. The mixed micellization behavior and surface properties of the phenothiazine-bile salt systems have been analyzed by conductivity and surface tension measurements. Application of different theoretical approaches to all the phenothiazine-bile salt mixtures shows a non-ideal behavior. Further, the spectroscopic techniques such as UV-visible and steady state fluorescence have been employed to study the binding of phenothiazines with bile salts. The stoichiometric ratios, binding constants (K), and free energy change (ΔG) for the phenothiazine-bile salt complexes were estimated from the Benesi-Hildebrand (B-H) double reciprocal plots obtained by using the changes in spectral intensities of phenothiazines on addition of bile salts. The results are discussed in the light of use of bile salts as promising drug delivery agents for phenothiazines and hence improve their bioavailabilty.

Interaction of amphiphilic drugs with human and bovine serum albumins.

To know the interaction of amphiphilic drugs nortriptyline hydrochloride (NOT) and promazine hydrochloride (PMZ) with serum albumins (i.e., human serum albumin (HSA) and bovine serum albumin (BSA)), techniques of UV-visible, fluorescence, and circular dichroism (CD) spectroscopies are used. The binding affinity is more in case of PMZ with both the serum albumins. The quenching rate constant (k(q)) values suggest a static quenching process for all the drug-serum albumin interactions. The UV-visible results show that the change in protein conformation of PMZ-serum albumin interactions are more prominent as compared to NOT-serum albumin interactions. The CD results also explain the conformational changes in the serum albumins on binding with the drugs. The increment in %α-helical structure is slightly more for drug-BSA complexes as compared to drug-HSA complexes.

Acepromazine pharmacokinetics: a forensic perspective.

Acepromazine (ACP) is a useful therapeutic drug, but is a prohibited substance in competition horses. The illicit use of ACP is difficult to detect due to its rapid metabolism, so this study investigated the ACP metabolite 2-(1-hydroxyethyl)promazine sulphoxide (HEPS) as a potential forensic marker. Acepromazine maleate, equivalent to 30mg of ACP, was given IV to 12 racing-bred geldings. Blood and urine were collected for 7days post-administration and analysed for ACP and HEPS by liquid chromatography-mass spectrometry (LC-MS). Acepromazine was quantifiable in plasma for up to 3h with little reaching the urine unmodified. Similar to previous studies, there was wide variation in the distribution and metabolism of ACP. The metabolite HEPS was quantifiable for up to 24h in plasma and 144h in urine. The metabolism of ACP to HEPS was fast and erratic, so the early phase of the HEPS emergence could not be modelled directly, but was assumed to be similar to the rate of disappearance of ACP. However, the relationship between peak plasma HEPS and the y-intercept of the kinetic model was strong (P=0.001, r(2)=0.72), allowing accurate determination of the formation pharmacokinetics of HEPS. Due to its rapid metabolism, testing of forensic samples for the parent drug is redundant with IV administration. The relatively long half-life of HEPS and its stable behaviour beyond the initial phase make it a valuable indicator of ACP use, and by determining the urine-to-plasma concentration ratios for HEPS, the approximate dose of ACP administration may be estimated.

Autoinduction of the metabolism of phenothiazine neuroleptics in a primary culture of human hepatocytes.

BACKGROUND: The metabolism of phenothiazine neuroleptics (promazine, perazine) in a primary culture of human hepatocytes after pretreatment of cells with those neuroleptics was studied. METHODS: The hepatocytes were pretreated with 25 µM promazine or perazine for 96 h. Then, the cells were incubated for 2, 4, 6, 8 and 24 h in the presence of neuroleptics. At the indicated time points, concentrations of phenothiazines and their metabolites (5-sulfoxides and N-desmethyl derivatives) were measured in the culture medium using HPLC with UV detection. RESULTS: Pretreatment of the primary culture of human hepatocytes with promazine or perazine resulted in accumulation of their metabolites in the culture medium. Such an effect was not observed in the case of control cultures (not pretreated with neuroleptics). CONCLUSION: The obtained results suggest that the tested phenothiazines may stimulate their own metabolism by inducing CYP1A2, CYP3A4 and CYP2C19 isoforms.

Comparative study of the efficiency of synthetic and natural mediators in laccase-assisted bleaching of eucalyptus kraft pulp.

The natural phenolic compounds syringaldehyde and vanillin were compared to the synthetic mediators 1-hydroxybenzotriazole, violuric acid and promazine in terms of boosting efficiency in a laccase-assisted biobleaching of eucalyptus kraft pulp. Violuric acid and 1-hydroxybenzotriazole revealed to be the most effective mediators of the bioprocess. Nevertheless, laccase-syringaldehyde system also improved the final pulp properties (28% delignification and 63.5% ISO brightness) compared to the process without mediator (23% and 61.5% respectively), in addition to insignificant denaturation effect over laccase. The efficiency of the biobleaching process was further related to changes in non-conventionally used optical and chromatic parameters of pulp, such as (L*), chroma (C*) and dye removal index (DRI) showing good correlation. Adverse coupling reactions of the natural phenolic mediators on pulp lignin were predicted by electrochemical studies, demonstrating the complexity of the laccase-mediator reaction on pulp.

Contribution of human cytochrome p-450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine.

1. The aim of the present study was to identify human cytochrome p-450 isoforms (CYPs) involved in 5-sulphoxidation and N-demethylation of the simplest phenothiazine neuroleptic promazine in human liver. 2. The experiments were performed in the following in vitro models: (A). a study of promazine metabolism in liver microsomes-(a). correlations between the rate of promazine metabolism and the level and activity of CYPs; (b). the effect of specific inhibitors on the rate of promazine metabolism (inhibitors: CYP1A2-furafylline, CYP2D6-quinidine, CYP2A6+CYP2E1-diethyldithiocarbamic acid, CYP2C9-sulfaphenazole, CYP2C19-ticlopidine, CYP3A4-ketoconazole); (B). promazine biotransformation by cDNA-expressed human CYPs (Supersomes 1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2E1, 3A4); (C). promazine metabolism in a primary culture of human hepatocytes treated with specific inducers (rifampicin-CYP3A4, CYP2B6 and CYP2C inducer, 2,3,7,8-tetrachlordibenzeno-p-dioxin (TCDD)-CYP1A1/1A2 inducer). 3. In human liver microsomes, the formation of promazine 5-sulphoxide and N-desmethylpromazine was significantly correlated with the level of CYP1A2 and ethoxyresorufin O-deethylase and acetanilide 4-hydroxylase activities, as well as with the level of CYP3A4 and cyclosporin A oxidase activity. Moreover, the formation of N-desmethylpromazine was correlated well with S-mephenytoin 4'-hydroxylation. 4. Furafylline (a CYP1A2 inhibitor) and ketoconazole (a CYP3A4 inhibitor) significantly decreased the rate of promazine 5-sulphoxidation, while furafylline and ticlopidine (a CYP2C19 inhibitor) significantly decreased the rate of promazine N-demethylation in human liver microsomes. 5. The cDNA-expressed human CYPs generated different amounts of promazine metabolites, but the rates of CYP isoforms to catalyse promazine metabolism at therapeutic concentration (10 microM) was as follows: 1A1>2B6>1A2>2C9>3A4>2E1>2A6>2D6>2C19 for 5-sulphoxidation and 2C19>2B6>1A1>1A2>2D6>3A4>2C9>2E1>2A6 for N-demethylation. The highest intrinsic clearance (V(max)/K(m)) was found for CYP1A subfamily, CYP3A4 and CYP2B6 in the case of 5- sulphoxidation, and for CYP2C19, CYP1A subfamily and CYP2B6 in the case of N-demethylation. 6. In a primary culture of human hepatocytes, TCDD (a CYP1A subfamily inducer), as well as rifampicin (mainly a CYP3A4 inducer) induced the formation of promazine 5-sulphoxide and N-desmethylpromazine. 7. Regarding the relative expression of various CYPs in human liver, the obtained results indicate that CYP1A2 and CYP3A4 are the main isoforms responsible for 5-sulphoxidation, while CYP1A2 and CYP2C19 are the basic isoforms that catalyse N-demethylation of promazine in human liver. Of the other isoforms studied, CYP2C9 and CYP3A4 contribute to a lesser degree to promazine 5-sulphoxidation and N-demethylation, respectively. The role of CYP2A6, CYP2B6, CYP2D6 and CYP2E1 in the investigated metabolic pathways of promazine seems negligible.

The contribution of cytochrome P-450 isoenzymes to the metabolism of phenothiazine neuroleptics.

The aim of the present study was to determine optimum conditions for studying promazine and perazine metabolism in rat liver microsomes, and to investigate the influence of specific cytochrome P-450 inhibitors on 5-sulfoxidation and N-demethylation of these neuroleptics. Based on the developed method, the metabolism of neuroleptics in liver microsomes was studied at linear dependence of product formation on time, and protein and substrate concentrations (incubation time: 10 min; concentration of microsomal proteins: promazine-0.7 mg ml(-1), perazine-0.5 mg ml(-1); substrate concentrations: promazine-25, 40 and 75 nmol ml(-1), perazine-20, 35, 50 nmol ml(-1)). A Dixon analysis of the metabolism of neuroleptics showed that quinine (a CYP2D1 inhibitor), metyrapone (a CYP2B1/B2 inhibitor) and alpha-naphthoflavone (a CYP1A1/2 inhibitor) affected, whereas erythromycin (a CYP3A inhibitor) and sulfaphenazole (a CYP2C inhibitor) did not change the neuroleptic biotransformation. N-Demethylation of promazine was competitively inhibited by quinine (K(i)=20 microM) and metyrapone (K(i)=83 microM), while that of perazine-by quinine (K(i)=46.5 microM), metyrapone (K(i)=46 microM) and alpha-naphthoflavone (K(i)=78.8 microM). 5-Sulfoxidation of promazine was inhibited only by quinine (K(i)=28.6 microM), whereas that of perazine-by quinine (K(i)=10 microM) and metyrapone (K(i)=96 microM). The results obtained are compared with our previous findings of analogous experiments concerning thioridazine, and with the data on other phenothiazines and species. In summary, it is proposed that N-demethylation of the mentioned phenothiazine neuroleptics in the rat is catalyzed by the isoenzymes CYP2D1, CYP2B2 and CYP1A2 (CYP1A2 does not refer to promazine). 5-Sulfoxidation of these drugs may be mediated by different isoenzymes, e.g. CYP2D1 (promazine and perazine), CYP2B2 (perazine) and CYP1A2 (thioridazine). Isoenzymes belonging to subfamilies CYP2C and CYP3A do not seem to be involved in the metabolism of the investigated neuroleptics in the rat. The results obtained point to the drug structure and species differences in the contribution of cytochrome P-450 isoenzymes to the metabolism of phenothiazines.

Effect of carbamazepine on the pharmacokinetics of promazine.

Combinations of neuroleptics and carbamazepine are administered to psychiatric patients in the therapy of mania, manic-depressive illness and schizophrenia. The present study was aimed at assessing the influence of carbamazepine on the pharmacokinetics of promazine. Male Wistar rats received promazine and/or carbamazepine twice daily for two weeks (promazine, 10 mg/kg ip; carbamazepine, 15 mg/kg ip during the 1st, and 20 mg/kg ip during the 2nd week of treatment). In a short time (1 h) after administration, carbamazepine had a tendency to increase the concentration of promazine in the blood plasma and brain. Lineweaver-Burk's analysis showed that carbamazepine added in vitro competitively inhibited the N-demethylation of promazine in liver microsomes, without affecting the sulphoxidation process. The effect was reflected in vivo (1 h) by an increased promazine/desmethylpromazine ratio. After a long time interval (6 h, 12 h), carbamazepine decreased the concentration of promazine and its metabolites. In vitro studies into the promazine metabolism, conducted on microsomes from rats treated with promazine and/or carbamazepine, did not show acceleration of its demethylation or sulphoxidation by carbamazepine. The obtained results suggest that induction of promazine metabolism by carbamazepine involves metabolic pathways other than N-demethylation or sulphoxidation. It has been concluded that when a phenothiazine neuroleptic, such as promazine, is administered jointly with carbamazepine, a slight increase in the neuroleptic concentration may be expected in a short time after administration, followed by its significant decrease.

The pharmacokinetics of promazine and its metabolites after acute and chronic administration to rats--a comparison with the pharmacokinetics of imipramine.

This study was aimed to investigate the pharmacokinetics of promazine (a phenothiazine analogue of imipramine) after its single and repeated administration. Male Wistar rats received promazine as a single injection (10 mg/kg ip) or they were treated chronically with the neuroleptic, once a day for two weeks. Plasma and brain concentration of promazine, desmethylpromazine and promazine sulphoxide were determined using the HPLC method devised by us. The results of the present study were compared with our earlier data obtained in analogous experiments with imipramine. The obtained data showed that the pharmacokinetics of promazine and imipramine was similar, though certain differences could be noticed. Both those drugs were unevenly distributed throughout the body, occurring in low concentrations in the blood plasma and reaching considerably higher concentrations in the brain. However, the uptake of promazine by the brain was more efficient than that of imipramine. The brain/plasma AUC ratio after a single dose amounted to 28.72 for promazine and 12.78 for imipramine. Their demethylated metabolites behaved in a similar way, where as the level of promazine sulphoxide in the brain was three times lower than that in the plasma. Chronic treatment with promazine or imipramine increased concentrations of the parent compounds and their demethylated metabolites, and prolonged their half-life in the plasma and brain. The plasma level of promazine sulphoxide did not change, and its brain level was decreased by chronic treatment with promazine. The half-life of promazine sulphoxide was prolonged in the plasma but shortened in the brain after repeated administration of promazine. The observed considerable amounts of desmethylpromazine and promazine sulphoxide, formed in vivo, suggest that the two compounds are major metabolites of promazine, and that the metabolic pattern of promazine in the rat and man is similar.

Kinetic evaluation of the oxidation of phenothiazine derivatives by methemoglobin and horseradish peroxidase in the presence of hydrogen peroxide. Implications for the reaction mechanisms.

The oxidation of ten 2-substituted 10-(3-(dimethylamino)propyl) phenothiazines (PHs) by methemoglobin (metHb) and horseradish peroxidase (HRP) in the presence of H2O2 was kinetically analysed based on an enzymic-chemical second-order reaction with substrate regeneration: PHs are oxidized enzymatically to their radical cations (PH+) which subsequently, in a second order reaction, react further to parent compound and PH-sulfoxide (PHSO). The enzymic reaction rate can be obtained from the accumulation curves of both radical cation formation and sulfoxide formation. In the case of chlorpromazine and promazine both methods gave similar reaction rates. The rate constant of PH+. decay could also be determined from the radical concentrations of their radicals. The rate constant of reaction of PHs with HRP compound II was also analysed. The logarithm of this rate constant correlated well with the Hammett sigma para and the Swain and Lupton F and R substituent constants, whereas no correlation with hydrophobic and steric parameters was found. This indicates that the interaction of PH with the porphyrin ring, which is the active site of HRP, is predominantly under electronic control. In the case of catalysis by hemoglobin (Hb), the formation of the reactive Hb form, ferry1Hb with a protein radical, appeared to be rate limiting in the oxidation of PHs by metHb-H2O2. Differences in the conversion rates of various PHs can be explained by a competition between their electron transfer reaction to the protein radical and the denaturation reaction(s) involving the protein radical. Our results confirm our earlier observation that the mechanism of oxidation by metHb-H2O2 differs from that of the classical peroxidases. In the former case, electron transfer from PH occurs most likely to a tyrosine residue on the globin part, whilst in the latter case electron transfer to the porphyrin moiety takes place.

In vivo toxicity and pulmonary effects of promazine and chlorpromazine in rats.

Cationic amphiphilic drugs induce a phospholipid storage disorder known as phospholipidosis. Halogenated analogs of the drugs are more potent inducers of phospholipidosis when compared to nonhalogenated analogs. Two such antipsychotic drugs, promazine and chlorpromazine, are effectively taken up by the lungs and induce lamellar inclusions in vitro. We compared the in vivo toxicity and efficacy of promazine and chlorpromazine to induce phospholipidosis in the lung and in pulmonary alveolar macrophages. Male Sprague-Dawley rats were given promazine or chlorpromazine (25 mg/kg/day, P.O., in water) for 5 weeks. Food intake was decreased in promazine- and chlorpromazine-treated rats, chlorpromazine rats being affected more than promazine rats. To minimize experimental error due to starvation, control rats were pair-fed. The body weight gain was decreased in chlorpromazine rats in comparison to pair-fed controls. Chlorpromazine-treated rats, but not promazine-treated rats, showed increased mortality over the 5-week treatment period. Histopathologic examination of lung revealed loss of alveolar macrophages with no other gross abnormalities in chlorpromazine-treated rats. Quantitative analysis of lung lavage also showed significant reduction in the number of macrophages. This finding is in contrast to other cationic amphiphilic drugs, which induce phospholipidosis as well as accumulation of alveolar macrophages. Phospholipid level increased in alveolar macrophages but not in lavaged lung following chlorpromazine treatment. Acid phosphatase activity in lavaged lung homogenate and macrophages of promazine- and chlorpromazine-treated rats, taken as an index of toxicity to cells, did not differ significantly from control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo photodegradation of chlorpromazine.

The in vivo photodegradation of chlorpromazine (CPZ) in the skin was investigated after systemic administration of 3H-CPZ to shaven Wistar rats and exposure to UV-A. Promazine (PZ) and 2-hydroxy-promazine (2-OH-PZ) appeared to be formed in irradiated rats, but not in the skin of rats kept in the dark. This indicates that upon irradiation with UV-A the PZ-radical is formed which can be held responsible for the photobinding to eye and skin constituents as observed earlier [Schoonderwoerd and Beijersbergen von Henegouwen (1987) Photochem. Photobiol. 46, 501-505]. Chlorpromazine-sulfoxide (CPZSO) is a major metabolite of CPZ. Less CPZSO was found in the skin of irradiated rats compared to those kept in the dark. As this appeared not to be caused by photobinding or photodegradation of CPZSO it can be concluded that CPZSO is not a photoproduct of CPZ under these experimental conditions. This study shows that the in vivo photodegradation of CPZ proceeds via the promazinyl radical rather than via the radical cation.

Metabolism and pharmacokinetic studies of propionylpromazine in horses.

The propionylpromazine concentrations in plasma after intramuscular administration to horses were determined using gas chromatography with nitrogen-phosphorus detection. After hydrolysis by beta-glucuronidase/arylsulphatase, the parent drug and three metabolites were detected in urine. The metabolites were identified as 2-(1-hydroxypropyl)promazine, 2-(1-propenyl)promazine and 7-hydroxypropionylpromazine by gas chromatography-mass spectrometry. No N-demethylated or sulphoxidated metabolites of propionylpromazine were observed in the horse urine.

Metabolism of chlorpromazine and promazine in vitro: isolation and characterization of N-oxidation products.

1. The syntheses of the secondary hydroxylamines of nor1chlorpromazine and nor1promazine via their corresponding primary hydroxylamines and oximes are described. 2. The N-oxidation products are unstable to analysis by g.l.c. without prior derivatization; the decomposition products and the structures of the trimethylsilyl (TMS) and trifluoroacetyl (TFA) derivatives were characterized by g.l.c.-mass spectrometry. 3. Chlorpromazine, promazine and their demethylated products were shown to undergo metabolic N- and alpha-C-oxidation, to yield hydroxylamines and carboxylic acids, on incubation with fortified 9000 g liver homogenates of male New Zealand white rabbits. 4. A condensation product, an artifact formed by reaction of the metabolically derived primary hydroxylamines with acetaldehyde, an impurity in the extraction solvent, diethyl ether, was identified. 5. N-hydroxynor1- and N-hydroxynor2chlorpromazine undergo metabolic reduction to the parent amines, and the secondary hydroxylamine undergoes N-demethylation to yield the corresponding primary hydroxylamine.

Interaction of promazine with human ceruloplasmin.

Promazine is enzymically oxidized by ceruloplasmin without reduction of the 610 nm absorption band of the enzyme. Fluoride inhibited the reaction in a non-competitive manner. The ceruloplasmin oxidase activity is markedly enhanced when promazine is added in the presence of NADH; possibly through a change in enzyme conformation.

Biomolecular photoalterations mediated by phenothiazine derivatives.

This survey focuses on recent developments in the field of the ultraviolet photochemistry and photobiology of phenothiazine derivatives. One of the major alterations introduced by this kind of photosensitized reaction is a covalent addition of the photosensitizer or one of its photoproducts onto the macromolecular target. This reaction has been observed with soluble and membrane proteins, lipids and DNA. In the latter case, the addition occurs at the level of guanine residues and leads to inhibition of DNA replication.

A theoretical study of the binding of phenothiazine derivatives to residues 82-93 of calmodulin.

A theoretical study was performed of the interaction of four phenothiazine derivatives, promethazine, promazine, trifluopromazine, and trifluoperazine, with a fragment (82-93) of calmodulin, held in the alpha-helical conformation. The computations were performed in the framework of the SIBFA 2 procedure (sum of interactions between fragments computed ab initio), which uses analytical formulas based on ab initio self-consistent field computations. The interaction energy is the sum of the intermolecular phenothiazine-oligopeptide interaction energy and of the separate intramolecular energy variations of the phenothiazine and of the side chains of the oligopeptide upon complex formation. The ordering of interaction energies of the four investigated phenothiazines parallels the ordering of their experimentally measured affinities for calmodulin, with a maximum affinity for trifluoperazine. The principal features of the trifluoperazine complex are a short hydrogen bond between the piperazinium proton and one anionic oxygen of Glu 87, and hydrophobic interactions between the piperazinium ring and Val 91 and between the methylene chain and Ala 88, together with partial insertion of the phenothiazine ring and the--CF3 substituent between Phe 89 and Phe 92.

Toxicity of promazine and chlorpromazine to isolated rat hepatocytes and its modification by liposome entrapment.

Isolated rat hepatocytes were used to determine the relationship between magnitude of uptake by cells and cytotoxic effects of chlorpromazine (CPZ) and promazine (PZ). Cell injury was evaluated by the extent of leakage of cytoplasmic and lysosomal enzymes from cells to surrounding medium and by cytopathic changes seen under surface scanning electron microscopy, after drug exposure. The drug uptake was time- and dose-dependent; cell preparations exposed to equal concentrations of either drug in the medium contained a twice greater concentration of CPZ than of PZ. Cytoplasmic and lysosomal enzyme leakage from cells exposed to 200 and 500 microM of CPZ showed significantly greater toxicity than control cells or those exposed to PZ at the same concentration. Surface activity of drugs was determined to calculate their surface excess. The surface pressure of CPZ is about twice that of PZ at equimolar concentration and correlated with extent of drug uptake and toxicity, suggesting that the surfactibility could play a role in bioavailability and toxicity of these drugs to liver cell membranes. Cytotoxicity was decreased by entrapment of CPZ inside liposomes; up to 40% for lactate dehydrogenase leakage and 47% of beta-glucuronidase, presenting further evidence for the potential use of liposomes.