Phenothiazine Tranquilizers Research Articles

Successful non-surgical treatment of priapism in a breeding stallion.

Priapism is an abnormally prolonged erection of the penis normally not associated with sexual desire. It can occur in horses following phenothiazine tranquilizer administration. In general, priapism therapy consists of slings, massage, diuretics, cholinergic blockade and surgery. A 17-year-old, 538-kg KWPN breeding stallion was referred with priapism of > 4 days duration. Priapism occurred on the farm after a single IM injection of 15 ml imidocarb for treatment of suspected piroplasmosis (Babesia PCR positive). The horse was referred to a clinic where he was treated with 12ml flunixin meglumine IV, 30ml dexamethasone IV, 5ml furosemide IM and nadroparine calcique SC. Hematology and biochemistry were within normal limits except for a slight elevation of ASAT, LHD and total bilirubin. He was correctly vaccinated against influenza/tetanus/equine herpes virus and negative for all equine venereal diseases. On arrival the body score was 7/9 and a completely normal systemic and reproductive exam except for a non-painful erect penis, which he was unable to retract. Surgical creation of a vascular shunt between the corpus cavernosum penis (CCP) and the corpus spongiosum (CS) was proposed but rejected. After sedation with detomidine and butorphanol IV,10 mg phenylephrine diluted in 5ml NaCl 0.9% was injected twice in the CCP in 24 hours, at 1cm dorso-caudal to the corona glandis of the penis. After the second injection, permanent detumescence was achieved.Paralysis/paraphimosis necessitated 2 months of meloxicam treatment and use of a penile suspensory device to keep the penis in position. An initial 4-week intense acupuncture treatment did not resolve the paraphimosis. During a 2-month period, 3 cold showers of 30 minutes each were applied daily, each time resulting in partial retraction. He also received 60 ml Vitamin B per os daily for 3 months. Seven months post-injury, semen could only be collected via pharmacologically induced ejaculation (100%). Despite his excellent libido, regular trials to collect semen on the dummy, using three different AVs and with the aid of systemic gabapentin, clomipramine, oxytocin, phenylbutazone, xylazine, gonadotropin, topical testosterone gel and hot compresses at the root of the penis never resulted in effective ejaculation. Ultrasonographic examination revealed multiple distinct hyperechogenic areas in the CC. Twenty months post injury the stallion, ejaculated for the first time on the dummy in a hot and tight Colorado AV while under clomipramine, oxytocin, phenylbutazone and xylazine medication. All medication was gradually discontinued over the ensuing month. Until today he has remained active as a fertile breeding stallion without using any medication. This case shows that non-surgical treatment for priapism can be a valid alternative for the stallion to return to a normal full-time breeding activity on the dummy.

Comparative Determination of Chlorpromazine in Pharmaceutical Injectable Veterinary and Human Formulations by Spectrophotometric and High Performance Liquid Chromatographic Methods

Background: Chlorpromazine (CPZ) is a phenothiazine tranquilizer used in humans and animals. Rapid determinationof the drug in pharmaceutical preparations is often needed. The aim of the study was to further examine and ascertainasimple spectrophotometric method in comparison with a high performance liquid chromatographic (HPLC) methodfor the determination of CPZ concentrations in injectable pharmaceutical formulations used in man and animals.Methods: Concentrations of CPZ in injectable pharmaceutical formulations for human and veterinary uses weredetermined by a modified spectrophotometric method and by an HPLC method with appropriate standard calibrationcurves. The spectrophotometric method of CPZ determinationwas conducted by diluting 0.1 ml of the veterinary(5%) or 0.3 ml of human (0.5%) formulations to 200 ml of 0.1N sulfuric acid. Four ml of the diluted CPZ samples orthe standard solutions were mixed with 2 ml of 50% sulfuric acid. Then an aliquot of 0.2 ml of 2% ferric nitrate wasadded to the mixture. After 15 minutes, the absorbance was measured at 530 nm against water and vehicle blanksusing a spectrophotometer. The HPLC method applied in the present study consisted of reversed phase gradientchromatography with a C18 column and the eluent was (A) 50 mmol NaH2PO4, pH 2.5 and (B) acetonitrile - 50mmol NaH2PO4, pH 2.5 (60:40 v/v), flow rate at 1 ml/min, with a gradient of 15-55% B in 10 min, to 100% B in20 min, and 280-nm UV detection. From the calibration curves of CPZ standards, the following were calculated:Limit of detection limit (LOD) = 3.3 x SD/slope; Limit of quantitation (LOQ) = 10 x SD/slope, where SD is thestandard deviation of response of CPZ concentrations of the calibration curves.Linear regression analysis and relatedcoefficients of correlations were applied on the calibration curves. Results: The calibration curves of CPZ againstwater or vehicle blanks as determined by the spectrophotometric method or by the HPLC method were linear withstrong correlations (r = and / or >0.99). Based on the calibration curves, limit of detection and limit of quantitation thespectrophotometric method were comparable to those of the HPLC one. The contents CPZ in human and veterinaryinjectable formulations as determined by the spectrophotometricmethod were in accordance (100.6% and 102%,respectively)to the concentrations claimed on the labels of the formulations.Conclusion: The present results introduce a simple spectrophotometric method that could be used for routinemeasurement of CPZ concentrations in pharmaceutical formulations, with the added benefits of linearity, precisionand cost effectiveness.

Effect of additives on mixed micellization of a phenothiazine drug promethazine hydrochloride and an ester-based pyridinium gemini surfactant

Promethazine hydrochloride (PMT) is a phenothiazine tranquilizer compound used as a sedative, analgesic, anticholinergic, antihistaminic and antipsychotic drug. The effect of various additives such as urea, glucose, glycine and sodium chloride (NaCl) on the mixed micellization of PMT and an ester-functionalized pyridinium gemini surfactant, (4, 4′-(propane-1, 3-diyl) bis (1-(2-(hexadecanoyl oxy) ethyl) dipyridinium bromide (16-3-16), has been studied at a constant temperature using surface tension, conductivity and fluorescence techniques. The different micellar and interfacial parameters were evaluated which signify the non-ideal behavior of all mixed systems. The thermodynamic studies revealed that the micellization and adsorption processes are spontaneous with the latter being more prominent than the former since the values of standard Gibbs free energy of adsorption ) are more negative than those of standard Gibbs free energy of micellization (). Besides, the excess free energy change of micellization () was determined which also showed negative values. These studies are specially aimed to get a deep understanding of the effect of different biologically significant molecules on the mixed micellization of the PMT-(16-3-16) micellar systems so as to ensure the bioavailability and effectiveness of the drug.

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.

Physicochemical studies of pyridinium gemini surfactants with promethazine hydrochloride in aqueous solution

The mixed micellization and interfacial behavior of pyridinium gemini surfactants, 1,1'-(1,1'-(ethane-1,2-diylbis-(sulfanediyl))bis(alkane-2,1-diyl))dipyridinium bromide, i.e., [12-(S-2-S)-12], [14-(S-2-S)-14], [16-(S-2-S)-16] with a phenothiazine tranquilizer drug, promethazine hydrochloride (PMT), has been investigated by conductivity, surface tension and steady state fluorescence measurements. Different spectroscopic techniques like fluorescence, UV-visible and NMR were also employed to understand the nature of interactions between the pyridinium gemini surfactants and PMT. The various micellar, interfacial and associated thermodynamic parameters for different mole fractions of PMT-pyridinium gemini surfactant mixtures have been evaluated. Synergism was observed in the mixed micelle as well as the monolayer formed by these mixtures. The fluorescence quenching experiment indicates that the interactions between PMT and surfactants are hydrophobic in nature. The UV-visible measurements reveal the distinct formation of a drug-surfactant complex. The detailed mechanism for the type of interactions was further studied by NMR titrations which show cation-π interactions between PMT and pyridinium gemini surfactant molecules.

Competition for plasma protein binding sites between phenothiazine tranquillizers and iminodibenzyl antidepressants

Journal Article Competition for plasma protein binding sites between phenothiazine tranquillizers and iminodibenzyl antidepressants Get access D Sharples D Sharples Department of Pharmacy, The University, Manchester, M13 9PL, U.K. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 27, Issue 5, May 1975, Pages 379–381, https://doi.org/10.1111/j.2042-7158.1975.tb09463.x Published: 12 April 2011 Article history Received: 20 November 1974 Published: 12 April 2011

Routine detection and identification in urine of stimulants, analgesics, antihistamines, local anaesthetics and other drugs, some of which may be used to modify performance in sport.

Abstract MANY sporting authorities throughout the world proscribe, in addition to the stimulants, other classes of drugs, e.g. the narcotics and phenothiazine tranquillizers. Present gas-liquid chromatographic procedures for the routine detection in urine of all these classes of drugs suffer from the disadvantage of using a variety of operating conditions (see for example Kazyak & Knoblock, 1963, who listed retention time data for 59 compounds using a single SE-30 column and temperatures from 115–250°, and also Street, 1967). The work of Beckett, Tucker & Moffat (1967) on stimulants is therefore now extended, using two isothermal GLC systems, to obtain retention data for 74 additional compounds. This allows the analysis of 116 compounds to be made using only three isothermal GLC systems. Drugs, other than those which may be used to modify performance in sport, are included since sportsmen may use them for medical reasons, e.g. phenacetin in analgesic preparations or a local anaesthetic for injury, and these may interfere with the dope control test.

Inhibitory Effect of Chlorpromazine on RANKL-Induced Osteoclastogenesis in Mouse Bone Marrow Cells

Chlorpromazine (CPZ), the first widely used phenothiazine tranquilizer, is shown to inhibit the action of intracellular calmodulin (CaM) and bone resorption in vivo and in vitro. In this study, CPZ (0.63 - 10 µM) dose-dependently inhibited the formation of tartrate-resistant acid phosphatase (TRAP) staining-positive osteoclast-like cells in mouse bone marrow cells (BMCs) treated with 1α,25(OH)(2)D(3) (10 nM) or soluble receptor activator of nuclear factor-κB ligand (s-RANKL) (20 ng/ml). Expressions of mRNA for the nuclear factor of activated T-cells c1 (NFATc1), a key regulator of osteoclast differentiation; dendritic cell-specific transmembrane protein (DC-STAMP), an essential protein for cell-cell fusion; and characteristic markers of osteoclasts such as TRAP, cathepsin K, carbonic anhydrase II, and calcitonin receptor in BMCs were up-regulated by s-RANKL and decreased by the addition of CPZ (5 µM) or the selective CaM antagonist W7, but not the inactive analog W5. The general CaM kinase (CaMK) inhibitor KN-93 and CaM-dependent phosphatase calcineurin inhibitor FK-506 also inhibited s-RANKL-induced osteoclastogenesis. Phenothiazines such as CPZ, trifluoperazine (TFPZ), and promethazine (PMZ) inhibited s-RANKL-induced osteoclast-like cell formation in mouse BMCs. Osteoclastogenesis inhibitory effects decreased in the order of TFPZ, CPZ, PMZ, depending on their anti-CaM potency. These findings suggest that CPZ inhibits RANKL-induced osteoclastogenesis by its anti-CaM action.

Effect of Electrolytes on the Cloud Point and Dye Solubilization of Promazine Hydrochloride Solutions

The effect of electrolytes on the micellar behavior of amphiphilic drug, promazine hydrochloride (PMZ)—a phenothiazine tranquillizer, has been investigated using cloud point (CP) and dye solubilization techniques. An increase in the pH of the PMZ solutions decreased the CP in the absence as well as presence of additives (NaCl, NaBr, KBr) due to deprotonation of the drug molecules. At constant pH (6.67), addition of sodium halides (NaF, NaCl, NaBr) and alkali metal bromides (LiBr, NaBr, KBr) caused an increase in CP and UV visible absorbance of the dye Sudan III. The behavior is explained on the basis of the ions' position in Hofmeister series and their hydrated radii. The CP increased with the addition of quaternary ammonium bromides due to adsorption/mixed-micelle formation; the order being: Bu < Pr < Et < Me. The experimental results have been interpreted in terms of electrostatic effect and interactions between additives and PMZ head groups.

Identification of Acepromazine in Hair: An Illustration of the Difficulties Encountered in Investigating Drug‐facilitated Crimes

After a drug-facilitated sexual assault (DFSA), a woman was found in a drowsy state at home. She remembered having drunk an unknown beverage by the accused. Blood samples (collected 8 hours after the DFSA), two glasses, and a teaspoon seized by the police were analyzed. Acepromazine, a phenothiazine tranquilizer used in human and veterinary medicine, was detected in the residue of one of the glasses. In spite of acepromazine absence in the victim's blood, the possible use of acepromazine in the DFSA was reported to the police. Two weeks later, a suspect admitted having orally administered acepromazine to the victim. Using a liquid chromatography-tandem mass spectrometry method, this compound was subsequently detected (31 pg/mg) in a sample of the victim's hair collected a month and a half after the DFSA. A potential short elimination half-life in humans and/or the well-known in vitro degradation of acepromazine could explain the negative blood result. DFSA toxicological investigations are challenging and can be complicated when a rather unusual substance is concerned. In particular, special care should be taken when interpreting the results, taking into account elimination and/or instability data, when available.

Cloud point extraction and preconcentration for the gas chromatography of phenothiazine tranquilizers in spiked human serum.

Cloud point extraction was successfully applied to the preconcentration of phenothiazine derivatives, such as pericyazine (PC), chlorpromazine (CP) and fluphenazine (FUL), for gas chromatography (GC). Phenothiazine derivatives were separated from surfactants by passing the surfactant-rich phase through a cation exchange column after cloud point extraction, permitting the determination of the phenothiazine derivatives extracted in the surfactant-rich phase by GC. The optimal condition for the cloud point extraction of phenothiazine derivatives was also investigated using Triton X-100, Triton X-114, and PONPE10. Triton X-114 provided the most efficient recovery of phenothiazine derivatives among the surfactants used. The addition of sodium chloride and excess ammonia to the sample solution resulted in a decrement of the recovery of the phenothiazine derivatives. The proposed method was applied to the determination of phenothiazine derivatives in spiked human serum by GC. The recoveries of PC, CP, and FUL in spiked human serum were 95.1%, 87.1%, and 84.7%, respectively.

Blood pressure and electrocardiographic effects of acepromazine in anaesthetized horses

Acepromazine, a phenothiazine tranquilizer, causes hypotension in standing horses (Parry et al. 1982). However, a retrospective study (Taylor & Young 1993) showed that acepromazine pre-anesthetic medication did not affect arterial blood pressure (MAP) in anaesthetized horses. This study examined the effects of acepromazine on MAP during romifidine–ketamine–halothane anaesthesia in horses anaesthetized for various surgical procedures. Forty-four horses were allocated by block randomization to groups A and B. Group A received acepromazine 0.05 mg kg−1 IM 30 minutes before induction of anaesthesia, group B did not. All horses received romifidine 0.1 mg kg−1 IV 5 minutes before anaesthesia was induced with diazepam 0.05 mg kg−1 and 2.2 mg kg−1 ketamine IV. The horses' trachea were intubated and horses breathed 50% oxygen and 50% nitrous oxide plus halothane (concentration adjusted as required clinically) from a circle breathing system. Nitrous oxide was discontinued after 10 minutes and analgesics, flunixin 1.1 mg kg−1 and either morphine 0.1 mg kg−1 or butorphanol 0.05 mg kg−1 (matched for horses undergoing the same procedure) administered IV. The facial or dorsal metatarsal artery was catheterized for direct measurement of MAP (every 10 min) and withdrawal of blood for gas analysis (every 30 min). The electrocardiogram (ECG) was monitored continuously with a 10 seconds printout obtained every 10 minutes. Intermittent positive pressure ventilation (IPPV) was instigated if PaCO2 exceeded 9.3 kPa (70 mm Hg). Dobutamine was infused (1.0–5.0 kg−1minute−1) if MAP 70 mm Hg. Mean age, weight and duration of anaesthesia were compared between the groups using a t-test for independent samples. Gender distribution and numbers of horses requiring IPPV or dobutamine were compared between groups using a chi-squared test (with Yates correction). To compare MAP over time, the area under the curve (MAPAUC) was calculated and compared between groups using a t-test. Horses receiving dobutamine were excluded from MAPAUC and MAP comparisons. The ECG printouts were examined for arrhythmias. There were no significant differences between groups (p > 0.05). Group A contained three stallions, 10 geldings and nine mares, aged 6.3 years (range 0.75–18). Group B comprised eight stallions, 11 geldings and three mares aged 7.3(1–16) years. Duration of anaesthesia was group A 97 (50–140) minutes, group B 99 (50–160) minutes. Eight horses in group A and three in group B required IPPV. Nine horses in group A and four in group B received dobutamine. Mean arterial pressure ranged from 60 to 128 mm Hg in group A and 58–96 mm Hg in group B. Mean MAPAUC was 5941 mm Hg minute−1 in group A, in B 6000 mm Hg minute−1. Atrial pre-mature complexes were recorded from one horse in group B. No other arrhythmias were detected. Although MAP was lower in the acepromazine group, this appeared unlikely to cause a clinical problem. The incidence of arrhythmias was too low to determine the influence of acepromazine in this study.

Highly Specific and Convenient Color Reaction for Methylenedioxymethamphetamine and Related Drugs Using Chromotropic Acid. Application as a Drug Screening Test

The color reaction of various drugs with chromotropic acid and sulfuric acid was examined. Methylenedioxymethamphetamine (MDMA) exhibited a red-violet color on treatment of an aqueous solution with sulfuric acid and chromotropic acid. The specificity of the reaction was examined using 65 drugs. The results showed that while related drugs with a methylenedioxyphenyl moiety, such as methylenedioxy-amphetamine and -N-ethylamphetamine, were all positive, 51 drugs including amphetamine, methamphetamine, opiates, cocaine, and phencyclidine were negative. The drugs exhibiting a positive reaction include tetrahydrocannabinol and related drugs, sulfur-containing drugs such as phenothiazine tranquilizers, and diphenhydramine. These results indicate that the present method is highly specific for MDMA and related drugs although its specificity is not absolute. The detection of MDMA in urine was investigated, and found to be possible using this method.

Anaesthesia of laboratory rabbits using etorphine/methotrimeprazine and midazolam

The use of etorphine (a potent mu-opioid), methotrimeprazine (a phenothiazine tranquilizer) and midazolam (a benzodiazepine) in laboratory rabbits is described. The central ear artery was cannulated under local anaesthesia using lignocaine/prilocaine cream, enabling cardiovascular monitoring in conscious animals. Anaesthesia was characterized by respiratory arrest, profound analgesia and a stable cardiovascular system (after commencing intermittent positive pressure ventilation). Reversal of anaesthesia with buprenorphine (a partial mu agonist) did not reduce the degree of post-operative respiratory depression, but shortened the period of unconsciousness considerably. This anesthetic regimen can only be recommended for rabbits that are free of respiratory disease and if facilities for IPPV are available.

Enzymatic oxidation of phenothiazines by lipoxygenase/H 2O 2 system

Lipoxygenase (LOX) (EC 1.13.11.12) oxidized a wide range of phenothiazine (Pt) tranquillizers to their corresponding radical cations in the presence of H 2O 2 by means of an enzymatic chemical second-order mechanism with substrate regeneration similar to that of horseradish peroxidase. The optimum pH of LOX for this hydroperoxidase activity was in the acid range (pH 3.0–4.0), as has been shown for other Pt oxidizing systems, such as peroxidase/H 2O 2 and haemoglobin. LOX showed Michaelis constants for Pt ranging from 1.4 to 8.5 mM and which, in some cases, e.g. trifluoperazine, displayed substrate inhibition. By contrast, it had a high affinity for H 2O 2 in the μM to mM range. A new, previously undescribed plot, which relates the enzymatic affinity and the apparent second-order decay of the cation radical, was developed to study the influence of the 2- and 10-substituents in the Pt ring. The implications of this new plot and the LOX-mediated Pt oxidation are also discussed.

Inhibition and induction of cytochrome P450 2B1 in rat liver by promazine and chlorpromazine

Phenothiazine tranquilizers have been associated with pharmacokinetic drug interactions in man. In this study the in vivo and in vitro effects of the clinically important phenothiazines promazine (PZ) and chlorpromazine (CPZ) on drug oxidations catalysed by specific cytochrome P450 (P450) enzymes were investigated in the rat. In vitro, the two drugs were relatively ineffective inhibitors of constitutive P450 activities, but were inhibitory toward the principal phenobarbital-inducible P450 2B1 and, to a lesser extent, P450 1A1. Administration of PZ and CPZ to male rats did not markedly influence the total microsomal P450 content of the liver. However, the quantitatively important male-specific P450 2C11 was down-regulated by CPZ and concomitant induction of P450 2B1 and associated 7-pentylresorufin O-depentylase activity were noted. A small increase in the activity of microsomal 7-ethylresorufin O-deethylase was also observed following administration of both drugs to rats, suggesting induction of P4501A1/2. Considered together, it is apparent that the two phenothiazines are preferential inhibitors and inducers of P450 2B1 in rat liver. Drug interactions in humans involving phenothiazines may reflect a combined effect of induction and inhibition processes as well as down-regulation of other P450s, such as that produced by CPZ on P450 2C11.

Trifluoperazine binding to porcine brain calmodulin and skeletal muscle troponin C

Binding of trifluoperazine (TFP), a phenothiazine tranquilizer, to porcine brain calmodulin (CaM) and rabbit skeletal muscle troponin C (Tn C) was measured by an automated high-performance liquid chromatography binding assay using a molecular sieving column; 10 micrograms of either protein per injection is sufficient for determining TFP binding, and results are comparable to those obtained by equilibrium dialysis. Very little binding was observed to either protein in the absence of Ca2+ while in the presence of Ca2+ both proteins bind 4 equiv of TFP. Other characteristics of TFP binding however are different for each protein. For CaM, half-maximal binding occurs at 5.8 microM TFP, the Hill coefficient is 0.82, and the fit of the data to the Scatchard equation is consistent with four independent TFP-binding sites. Binding of one melittin displaces two TFP from CaM. Thus, there are two recognizable classes of TFP-binding sites: those that are displaced by melittin and those that are not. TFP causes an increase in the Ca2+ affinity of CaM, and three Ca2+ must be bound to CaM for TFP binding to occur. The studies also yielded a measure of the intrinsic affinity of three of CaM's Ca2(+)-binding sites that is in agreement with previous reports. For troponin C, half-maximal binding occurs at 16 microM TFP, the Hill coefficient is 1.7, and the data best fit the Adair equation for four binding sites. The measured constants K1, K2, K3, and K4 were 2.5 X 10(4), 6.6 X 10(3), 5.8 X 10(5), and 2.0 X 10(5) M-1, respectively, in 1 mM Ca2+ and were similar when Mg2+ was additionally included. TFP also increases troponin C's Ca2+ affinity, and it is the low-affinity, Ca2(+)-specific binding sites that are affected. These studies yielded a measure of the intrinsic affinity of these Ca2(+)-binding sites that is in agreement with previous measurements.

In vitro inhibition of hepatic drug oxidation by thioridazine : Kinetic analysis of the inhibition of cytochrome p-450 isoform-specific reactions

The phenothiazine tranquilizer thioridazine has been associated with drug interactions in man. This study investigated the capacity of the drug to inhibit hepatic drug oxidations mediated by cytochromes P-450 (P-450) in microsomes in vitro. Thioridazine was a potent linear mixed-type inhibitor of P-450b-dependent 7-pentoxyresorufin O-depentylase activity in phenobarbital-induced rat liver. The kinetic analysis revealed the enzyme-substrate dissociation constant ( K s ) to be 1.6 μM whereas the dissociation constant of the enzyme-inhibitor complex ( K i) was 0.11 μM. In contrast, 7-ethoxyresorufin O-deethylase activity (mediated by P-450c) in β-naphthoflavone-induced rat hepatic microsomes was inhibited to a lesser extent ( K i = 2.4 μM) in relation to the K s value (0.5 μM). Spectral studies indicated that the efficiency of thioridazine binding in phenobarbital-induced microsomes was about 25-fold greater than in microsomes from β-naphthoflavone-induced rat liver. This finding is consistent with the relative capacity of thioridazine to inhibit oxidase activities catalysed by P-450b and P-450c. Mixed-function oxidase activities catalysed by other P-450s were also inhibited by thioridazine, although to a lesser extent than those catalysed by forms b and c. Thus, the 6β- and 16β-hydroxylations of androst-4-ene-3, 17-dione in hepatic microsomes from untreated rats were inhibited to a similar extent (I 50S = 52 and 43 μM, respectively). The 7α- and 16α-hydroxylase pathways were approximately only half as susceptible to inhibition by thioridazine. These findings demonstrate the capacity of thioridazine to inhibit a range of P-450-dependent drug oxidations, with those catalysed by forms b and c most susceptible. The present study strongly suggests that drug interactions elicited by thioridazine are most likely a consequence of inhibitory interactions with P-450 enzymes.

Inhibition of hepatic drug metabolism by phenothiazine tranquilizers: quantitative structure-activity relationships and selective inhibition of cytochrome P-450 isoform-specific activities.

Twelve phenothiazine tranquilizers were investigated for the capacity to inhibit rat hepatic microsomal cytochrome P-450 (P-450) isoform-specific drug oxidation in vitro. All congeners were substituted in the 2-(carbocyclic) and 10- (thiazinyl nitrogen of the thiazine ring) positions. Cytochrome P-450 PB-B-mediated 7-pentylresorufin O-depentylase and P-450 BNF-B-mediated 7-ethylresorufin O-deethylase activities were effectively inhibited by most of the compounds. Structure-activity correlations revealed the apparent importance of the lipophilicity of the 2-substituent, and the negative effect of flexibility in the 10-position substituent, on anti-P-450 PB-B potency. On the other hand, inhibition of P-450 BNF-B activity was promoted by bulkiness and branching within the 10-substituent and the shape/bulk of the 2-group. From this analysis it is likely that the active site of P-450 PB-B is relatively small with at least one lipophilic region that may be involved in substrate and inhibitor binding. The active site of P-450 BNF-B is relatively large, and steric properties, rather than lipophilic character, appear to determine inhibition by phenothiazines. Derivatives with piperidinyl and piperazinyl ring systems in the 10-position were relatively active inhibitors of P-450 PCN-E (or an immunochemically related form of P-450) that catalyzes androst-4-ene-3,17-dione 6 beta-hydroxylation, and P-450 UT-A-mediated 16 alpha-hydroxylase activity. In contrast, steroid 7 alpha-hydroxylation (P-450 UT-F) and N-nitrosodimethylamine N-demethylation (P-450j) were refractory to inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

X-ray studies on phospholipid bilayers. VIII. Interactions with chlorpromazine.HCl.

Chlorpromazine is a widely used phenothiazine tranquilizer known to alter the shape of normal erythrocytes and their osmotic fragility. In order to understand the nature of the interactions chlorpromazine.HCl (CPZ.HCl) was made to interact with phospholipid bilayers formed by dimyristoylphosphatidylethanolamine (DMPE) and dimyristoylphosphatidylcholine (DMPC). This study was carried out by X-ray diffraction on crystalline powders of various molar mixtures of CPZ.HCl with DMPE and DMPC, with and without water. It was found that CPZ.HCl significatively affects the bilayer structure of DMPC in the presence of water, but not that of DMPE.