Acitretin.

Acitretin, a synthetic retinoid, is the pharmacologically active metabolite of etretinate. It is currently approved by the US Food and Drug Administration for the treatment of severe psoriasis in adults and has been established as a second-line therapy for the treatment of psoriasis resistant to the use of topical therapy. It is also an option for generalized pustular psoriasis, palmoplantar pustulosis, exfoliative erythrodermic psoriasis, and severe psoriasis in the setting of acitretin. It also has been shown to have chemo-preventative characteristics. Acitretin is limited by its teratogenicity and therefore considered inappropriate in most female patients of childbearing age. Common side effects include mucocutaneous dryness and elevated triglycerides.

The effects of alcohol on the metabolism and toxicology of anti-psoriasis drugs.

INTRODUCTION: Alcohol has long been suspected to be a triggering and precipitating factor of psoriasis. Alcohol misuse is common in patients with moderate-to-severe psoriasis and appears to impair treatment outcome. AREAS COVERED: In this article, the authors review the available data regarding the metabolic and toxicological interactions between anti-psoriasis systemic drugs and ethanol and/or alcoholic beverages. Special attention is given to the influence of alcohol consumption on the hepatotoxic risk of some anti-psoriasis drugs. The article was prepared using a MEDLINE literature search. EXPERT OPINION: The available knowledge highlights the existence of a few significant pharmacological interactions, such as the reduced exposure to cyclosporine by red wine, the possible increase of cyclosporine levels following a heavy acute alcohol intake, and, especially, the conversion of acitretin to etretinate, in the presence of ethanol, with important implications in females of child-bearing potential. There are limited data on the contributing role of alcohol in the hepatotoxicity induced by some anti-psoriasis drugs and the existing information on this topic is still controversial. However, further investigation is needed to assess the relevance of interactions between alcohol consumption and drug therapy for psoriasis, under both pharmacological and toxicological perspectives. Long-term prospective studies on large cohorts of patients are warranted to disclose the actual significance of such potential interactions in clinical practice.

Vitamin A: a multifunctional tool for development.

Extensive research carried out over the last 100 years has established that the fat-soluble organic compound vitamin A plays crucial roles in early development, organogenesis, cell proliferation, differentiation and apoptosis as well as in tissue homeostasis. Given its importance during development, the delivery of vitamin A to the embryo is very tightly regulated with perturbations leading to severe malformations. This review discusses the roles of vitamin A during human development and the molecular mechanisms controlling its biological effects, hence bridging the gap between human development and molecular genetic work carried out in animal models. Vitamin A delivery during pregnancy and its developmental teratology in humans are thus discussed alongside work on model organisms, such as chicken or mice, revealing the molecular layout and functions of vitamin A metabolism and signaling. We conclude that, during development, vitamin A-derived signals are very tightly controlled in time and space and that this complex regulation is achieved by elaborate autoregulatory loops and by sophisticated interactions with other signaling cascades.

Acitretin is converted to etretinate only during concomitant alcohol intake.

BACKGROUND: Acitretin has replaced etretinate in the treatment of various disorders of keratinization due to a considerably shorter terminal half-life. Possible esterification of acitretin to etretinate in the presence of ethanol has been reported. OBJECTIVES: To determine the plasma concentrations of etretinate as a metabolite in patients with various disorders of keratinization after multiple acitretin dosing, and to assess the influence of alcohol consumption using a questionnaire. In addition, to study the influence of alcohol consumption on the risk of metabolic formation of etretinate. PATIENTS/METHODS: Eighty-six acitretin (Neotigason(R), Roche)-treated outpatients from three centres provided pre-dose (trough) samples for determining plasma concentrations of acitretin and its metabolites 13-cis-acitretin and etretinate. Patients received acitretin doses of between 0.1 and 1.3 mg kg-1 daily. The concentrations of etretinate, acitretin and 13-cis-acitretin were determined by reverse-phase high-performance liquid chromatography. RESULTS: Of the 86 patients, 30 had detectable plasma etretinate levels. No etretinate was found in 20 patients who reported that they never drank alcohol, while etretinate was found in all 16 patients with an average weekly alcohol consumption of > 200 g ethanol, corresponding to about 15 U (1 U equals half a pint of standard beer or a wine glass of non-fortified wine). Etretinate was detected in 14 of 50 patients with a moderate weekly alcohol intake of up to 200 g ethanol. A trend linking higher alcohol intake with both higher risk of etretinate formation and higher etretinate levels was observed. The study also revealed that the ethylesterification only relates to acitretin (13-trans-) and not to the main metabolite 13-cis-acitretin, although the latter compound showed higher plasma trough concentration levels at steady state. CONCLUSIONS: Owing to the teratogenic potential and possible side-effects of oral retinoids, fertile women especially should be informed about the importance of strict alcohol abstinence during treatment and for at least 2 months after stopping therapy. In case of non-compliance with alcohol abstinence a post-therapy contraceptive period of 2-3 years should be recommended.

In vitro metabolism of acitretin by human liver microsomes: evidence of an acitretinoyl-coenzyme A thioester conjugate in the transesterification to etretinate.

The aromatic retinoid acitretin is the primary active metabolite of etretinate, and in this study we investigated the ethyl esterification of acitretin to etretinate using [(14)C]acitretin and human liver microsomes. Samples were analysed by TLC, HPLC, and LC-MS. Essential requirements for the transesterification reaction were identified and included viable microsomal protein, ATP, CoASH, and ethanol. Human liver microsomes catalysed formation of acitretinoyl-CoA at the rate of 0.08 +/- 0.02 nmol/min/mg (mean +/- SD, N = 10). Acitretinoyl-CoA was pivotal for the transesterification to etretinate and in the presence of methanol, ethanol, n-propanol, n-butanol, and hexanol, the corresponding esters, namely methyl-, ethyl (etretinate)-, propyl-, butyl-, and hexyl-acitretinate, were formed. On average, 1.7% of the acitretin present in the incubation was converted to etretinate in the presence of ethanol. In the absence of ethanol, transesterification did not proceed. Inhibition of the ester hydrolysis of etretinate by bis-p-nitrophenylphosphate (BNPP, 1 mM) prevented futile cycling of etretinate via acitretinoyl-CoA. An additional finding was that acitretin (15-30 microM) activated significantly human liver microsomal long-chain fatty acid-CoA ligase (E.C.6.2.1.3, LCL), resulting in enhanced formation of palmitoyl-CoA. This study demonstrated that in the presence of ethanol the ethyl esterification of acitretin to etretinate proceeds via formation of acitretinoyl-CoA. Predicting clearance of acitretin in vivo via this unique metabolic pathway will be a challenge, as the intracellular concentration of ethanol could never be predicted with any degree of accuracy in humans.

Acitretin in psoriasis: an overview of adverse effects.

Oral retinoids are among the drugs of choice for pustular and erythrodermic psoriasis. In addition, retinoids are effective in combination with other topical and systemic agents for the treatment of plaque-type psoriasis. Acitretin, the active retinoid metabolite, has replaced etretinate in retinoid therapy of psoriasis because of its more favorable pharmacokinetic profile, including a significantly shorter half-life. Retinoids, including acitretin, are potent teratogens, leading to strict requirements for pregnancy prevention during and after their use. Other retinoid side effects are generally preventable or manageable through proper patient selection, dose adjustments, and routine monitoring. Mucocutaneous side effects such as cheilitis and hair loss are the most common dose-dependent side effects, requiring dose reduction in some patients. Less common effects such as hepatotoxicity, serum lipid alterations, pancreatitis, and possible skeletal effects are also discussed.

Mechanistic studies on the ethyl-esterification of acitretin by human liver preparations in vitro.

Studies have been performed with human liver microsome preparations in vitro, to investigate the reaction mechanisms involved in the conversion of acitretin to the corresponding ethyl ester, etretinate. The results indicate that: Three fresh samples of human liver, which had been stored in liquid nitrogen for up to 8 months, all produced traces of etretinate (5.8 +/- 0.8 ng/ml) in the presence of ethanol but not when the acitretin was added in acetone, or when the sample was denatured by preheating. Studies with pooled human liver microsomes, to identify the cellular location of the enzymes and the co-factors involved in this esterification, indicate a primary requirement for both ethanol and CoA + ATP with a secondary potentiation in the presence of an NADPH regenerating system. A possible explanation for these finding is that the microsomal ligase enzymes form an intermediate ester between CoA and acitretin, which is then trans-esterified by the ethanol. The low formation with CoA + ATP may indicate that second stage of this process occurs spontaneously, with the NADPH potentiation suggesting that it could also be mediated enzymically.

Simultaneous determination of etretinate, acitretin and their metabolites in perfusate, perfusate plasma, bile or hepatic tissue with reversed-phase high-performance liquid chromatography.

Etretinate is a synthetic aromatic retinoid used in the treatment of psoriasis and other disorders affecting the skin. Acitretin is the primary active metabolite of etretinate. The in situ perfused rat liver model was used to study the first-pass hepatic metabolism of etretinate and acitretin and a reliable method of quantifying etretinate and its metabolites was needed. Previously published assays allow for the simultaneous quantitation of etretinate and acitretin in blood or plasma. This paper describes an accurate and reliable reversed-phase HPLC method for the determination of etretinate, acitretin and their metabolites in whole perfusate, plasma, bile and hepatic tissue.

Acitretin biotransformation into etretinate: role of ethanol on in vitro hepatic metabolism.

The aim of this study was to investigate the possible esterification of acitretin into etretinate by using hepatocytes in primary culture from the rat, monkey, dog and man. With rat and human hepatocytes, etretinate was detectable only when ethanol was co-administered with acitretin. With monkey and dog cells, traces of etretinate were found without ethanol addition, but the esterification of acitretin was highly enhanced by ethanol. The metabolic profile was not changed when cells were pre-incubated with ethanol. Therefore acitretin seems to act rather as a substrate than an enzymatic inducer.

Conversion of acitretin to etretinate in psoriatic patients is influenced by ethanol.

Acitretin has recently been introduced to replace etretinate in the treatment of severe psoriasis due to a considerable shorter terminal half-life. The previously recommended 2-month anticonceptive period after acitretin treatment has been extended to 2 years after the detection of etretinate in certain acitretin recipients. In the present study, 10 patients with severe psoriasis were treated with 30 mg acitretin daily for 3 months. Seven patients had detectable mean steady-state plasma etretinate concentrations in the range of 2.5 to 56.7 ng/ml. Four of the patients showed teratogenic levels of plasma etretinate. Consumption of alcohol appeared to be an important contributing factor for the formation of etretinate. As judged from the dose- and body-weight-normalized AUC values (AUCcor) there was a great inter-individual variation (sixfold) in the systemic availability of acitretin. After discontinuation of therapy, the rate of elimination of both acitretin (t1/2 range 1.0 to 25.4 d) and 13-cis-acitretin (t1/2 range 1.5 to 25.7 d) was found to be related to the observed mean steady-state level of etretinate as evidenced by a longer terminal t1/2 of patients with high levels of etretinate in plasma. A mean terminal elimination half-life of etretinate was found to be 45.7 d +/- 10.6 (mean +/- SD; range 27.0 to 59.3 d). The risk of metabolic formation of etretinate in acitretin recipients makes it impossible to draw any definite conclusion with regard to recommendation of length of anticonceptive period following acitretin therapy in psoriatics. Monitoring of plasma etretinate levels in acitretin-treated fertile women is advisable.

Skin, adipose tissue and plasma levels of acitretin with rare occurrence of esterified acitretin during long-term treatment.

In a previous study acitretin and its 13-cis-metabolite were monitored in the plasma and epidermis of healthy volunteers. They were given 50 mg of trans-acitretin daily. No drug accumulation was observed in the skin, nor in the plasma. The purpose of the present study was to extend the data from non-psoriatic to psoriatic (n = 11) subjects, treated for at least 1 month with 25 mg acitretin. Plasma, skin biopsies and subcutaneous fat samples were analysed using HPLC. Trough levels of acitretin in skin were below the quantification limit, increasing to 28 +/- 16 ng/g within 5 h after dosing. Fat tissue levels exceeded those of skin, with values of 98 +/- 71 ng/g within 5 h after drug intake. In 2 patients, additional samples were taken 3 days post-therapy. Here, concentrations were below the quantification limit in adipose tissue, confirming that acitretin is not stored in subcutaneous fat. Esterification of acitretin into etretinate was observed in 2 subjects. This observation illustrates the recently described new metabolic pathway for acitretin. On both occasions, the unexpected ethylester metabolite was extensively stored in fat tissue.

Effect of etretinate on cyclosporin metabolism in vitro.

Cyclosporin (CyA) is an effective treatment for psoriasis, including cases unresponsive to other therapies. The major side-effect of CyA treatment is dose-related nephrotoxicity. Combinations of CyA and etretinate (Et) have been tested with a view to reducing CyA dose requirements, and therefore minimizing adverse effects. We have studied the effect of Et on the cytochrome P-450-mediated metabolism of CyA. Microsomes prepared from histologically normal human (obtained from four cadaver kidney transplant donors; all male; age range 21-56) were incubated with CyA and various concentrations of Et. Metabolism was quantified by high-performance liquid chromatography with radiometric detection, and metabolites tentatively identified from the retention times of authentic standards. After 30 min incubation of CyA and microsomal protein at 37 degrees C, 10.1 +/- 3.0% (mean +/- SD) 3H-CyA was converted to the monohydroxylated metabolites M1 and M17, and 3.3 +/- 0.8% to the N-demethylated metabolite M21. At an Et concentration of 100 microM inhibition of CyA hydroxylase and N-demethylase was < 20%. This study indicates that there is no metabolic interaction between CyA and Et in vitro; it is likely that the two drugs are metabolized by different P-450 isoenzymes.

A potentially new metabolic pathway: ethyl esterification of acitretin.

1. The acidic retinoid, acitretin, was esterified to etretinate (ethyl ester) by rat and human liver 12,000 g supernatant. The amount of etretinate formed was increased by adding ethanol to the rat preparation. 2. This esterification almost certainly involves enzymic catalysis, and the amounts of etretinate formed were increased by the use of fresh rat liver. 3. Co-administration of acitretin and ethanol to rats resulted in a maximum plasma concentration of etretinate at approximately 1 h after dosing. Secondary maxima were induced by administering ethanol alone at 5 and 8 h after dosing with acitretin. 4. Comparison of acitretin and etretinate concentrations in rat portal and jugular vein plasma after ethanol administration indicated that the ester was formed mainly systematically, rather than during absorption. 5. The results of our study in the rat could indicate that the presence of etretinate in plasma of some patients being treated with acitretin may result from the intake of alcohol.

Acitretin (Neotigason). A review of pharmacokinetics and teratogenicity and hypothesis on metabolic pathways.

Acitretin was introduced as a replacement for etretinate, the ethyl ester of acitretin. Acitretin is eliminated at a much faster rate than etretinate. Although both drugs are teratogens, the replacement was important especially as it allowed for a much shorter post-medication period in which pregnancy should be precluded. Recent findings showed the presence of etretinate in the plasma of acitretin-treated patients. This article gives a review of known metabolic pathways of the retinoids and tries to elucidate the possible conversion of acitretin into etretinate after acitretin ingestion.

A newly discovered xenobiotic metabolic pathway: ethyl ester formation.

Formation of etretinate, ethyl ester of acitretin, can be confirmed in vitro and in vivo using acitretin as the substrate. Etretinate was identified by LC/MS. The in vitro incubation was performed using rat and human liver 12,000 g supernatant, and the in vivo experiment was conducted in rats after oral dosing of acitretin. The ethyl ester formation was greatly enhanced by addition of or dosing with ethanol.

Uptake of the aromatic retinoids Ro 10-9359 (etretinate) and Ro 10-1670 (acitretin), its main metabolite, delivered to cultured human fibroblasts by serum proteins. Lack of evidence for perturbation of LDL catabolism.

Etretinate or acitretin are efficiently delivered to cultured human fibroblasts in the presence of low density lipoproteins, high density lipoproteins or human serum albumin. In contrast to acitretin, delivery of etretinate to fibroblasts is more efficiently achieved with human serum albumin than with lipoproteins. The uptake of etretinate and acitretin via low density lipoproteins delivery, does not take place via the low density lipoprotein-receptor endocytotic pathway but mostly through a passive exchange with the plasma membrane. However, in contrast to acitretin, the exchange of etretinate seems to occur alter binding of etretinate-loaded low density lipoproteins to the apolipoprotein B receptors. No differences are observed in binding, internalization and degradation of native, etretinate-loaded low density lipoproteins and acitretin-loaded low density lipoproteins, suggesting that the presence of these retinoids in low density lipoproteins does not alter their processing by the cells. Furthermore, the presence of these retinoids in the cells does not notably affect, under our experimental conditions, the catabolism of native low density lipoproteins.

Pharmacokinetics of etretinate in psoriatic patients with liver fibrosis.

A study of the pharmacokinetics of etretinate in 7 psoriatic patients with liver fibrosis or liver cirrhosis is reported. Maximum plasma concentrations occurred within 1.5-4.0 hr. Absorption lag-times ranged from 0.3-2.5 hr, whereas the apparent absorption first order half-times (t1/2ka) were within the range of 0.3-1.2 hr. As judged from the AUC-values corrected for dose and body weight a six-fold interindividual variation existed with regard to the systemic availability of etretinate. Absorption and disposition rates of etretinate in subjects with hepatic fibrosis increasing to cirrhosis were not significantly altered compared with previous results in psoriatic patients with normal liver function.

Biotransformation of etretinate and developmental toxicity of etretin and other aromatic retinoids in teratogenesis bioassays.

Developmental toxicity of the anti-psoriatic drug etretinate (Tegison) and some features of its metabolic conversion to etretin and isoetretin were investigated in in vivo and in vitro teratogenesis bioassays. We found that a single dose of etretinate administered orally to pregnant mice on day 11 of gestation was a potent teratogen (ED50 = 26 mg/kg). Etretin (acitretin, Neotigason), given as a single dose, was about 8-fold less active as a teratogen than etretinate. A ring substituted congener of etretinate, Ro 11-4768, was essentially inactive under similar conditions. Although the mechanisms which operate to make Ro 11-4768 inactive in teratogenesis are unknown and intriguing, it is suggested that the differences between etretinate and etretin may be dependent on individual pharmacokinetic characteristics. The in vitro chondrogenesis bioassay confirmed previous reports that the presence of an acidic endgroup was necessary for suppression of chondrogenesis, and that on that basis etretin was an active inhibitor of chondrogenesis, whereas etretinate was not. Introduction of esterase into the culture medium resulted in complete hydrolysis of etretinate and a quantitative conversion to acid congeners sufficient to account for an appropriate suppression in chondrogenesis. Although limb bud cells were virtually incapable of converting etretinate to etretin in the absence of exogenous esterase, they did influence the metabolism so that in the presence of esterase, isoetretin rather than etretin was the major endproduct of etretinate hydrolysis. Since etretinate therapy endangers the conceptus for a prolonged period of time even after cessation of therapy, further studies are necessary to determine the nature and the extent of hazard posed by the storage and/or metabolism of etretinate.