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.

Evaluation of the transfusion safety of blood products and determination of plasma concentrations of acitretin and etretinate in patients receiving transfusions.

BACKGROUND: Acitretin and etretinate are potentially teratogenic. Many people taking acitretin for psoriasis have donated blood during the deferral period in Korea. Therefore, many of the blood products from these donors treated with acitretin have been circulated in Korea. STUDY DESIGN AND METHODS: A high-performance liquid chromatography system (HP 1050, Agilent Technologies) was used to measure the drug concentrations in five blood products and in patients. Sixty patients taking acitretin were enrolled to determine their plasma drug levels. Forty-one female patients were recruited to investigate the residual plasma levels of acitretin and etretinate in relation to their teratogenicity. We calculated the elimination rate of acitretin and etretinate during the manufacturing process. RESULTS: Sixty individuals taking acitretin expressed variable acitretin (<2.0-206.8 ng/mL) and etretinate levels (<2.0-9.1 ng/mL). All patients that had a transfusion had concentrations of acitretin and etretinate lower than the lower limit of quantification (LLOQ; 2 ng/mL). The concentrations of acitretin and etretinate in five blood products were less than the LLOQ. Approximately 98.84 percent (log value, 1.94) of the acitretin and 99.93 percent (log value, 3.14) of the etretinate was eliminated during the manufacturing process of albumin. More than 99.99 percent (log values, 5.95-15.76) of acitretin and etretinate was eliminated during the manufacturing processing of immunoglobulin and blood coagulation factors. CONCLUSIONS: We confirmed the effective manufacturing processing of various blood products. We also demonstrated that individuals receiving transfusions with blood products originating from donors treated with acitretin were not at risk for significant exposure to the acitretin and etretinate.

Retinoides en dermatología / Retinoids in Dermatology

Desde su introducción en la Dermatología hace 60 años, los retinoides han adquirido la condición de fármaco indispensable en nuestra especialidad. Este hecho se debe tanto a la observación de resultados efectivos en un alto número de procesos cutáneos como por las innovaciones que se han realizado tanto en su estructura como en su formulación. En la actualidad su efectividad y seguridad está bien establecida, tanto en formulaciones tópicas como sistémicas, en acné, psoriasis y fotoenvejecimiento. En los últimos años se han descrito nuevas indicaciones de los retinoides en dermatología entre las que caben destacar su uso en el tratamiento del cáncer cutáneo, o con fines cosméticos con buenos resultados en cicatrización de las heridas, estrías cutáneas en fases iniciales o alopecia androgenética. Los avances farmacológicos han permitido derivados de la vitamina A más efectivos y con menos efectos adversos. Tretinoina, aún con una mayor actividad irritante, sigue siendo el fármaco más efectivo por vía tópica en fotoenvejecimiento y cáncer cutáneo. Isotretinoina por vía oral es el fármaco de elección en el acné crónico y severo, adapaleno es la formulación tópica mejor tolerada en el acné, tazaroteno es el primer retinoide tópico con efectividad en psoriasis, etretinato y acitretino se consideran de elección en el tratamiento sistémico del psoriasis. Por último, se han descrito de forma reciente nuevas moléculas que han ampliado las indicaciones de los retinoides en dermatología, son alitretinoina para el sarcoma de Kaposi asociado a SIDA y bexaroteno para el linfoma cutáneo de células T (AU)

Use of the deconvolution principle in the estimation of absorption and pre-systemic intestinal elimination of drugs.

The deconvolution principle was used to evaluate the extent of absorption and first-pass elimination of selected drugs. In the first example, deconvolution of the portal blood profiles of etretinate (ET, a synthetic retinoid) indicated that there was significant gut-wall conversion of ET to acitretin (ETA, the primary metabolite of ET) during a 60-min intestinal perfusion of ET. In the second example, deconvolution was used to confirm that the extent of carbovir disappearing from the gastrointestinal lumen was matched by the extent of carbovir appearance in the portal blood. Thus, deconvolution has several important applications in the study of absorption and intestinal first-pass metabolism.

[Trans-acitretin is metabolized back to etretinate. Importance for oral retinoid therapy]. / Trans-Acitretin wird in Etretinat rückmetabolisiert. Bedeutung für die orale Retinoidtherapie.

The oral retinoid etretinate (Tigason) has recently been replaced by trans-acitretin (Neotigason) in the treatment of severe psoriasis, primarily because of its short half-life and the assumption that a shorter period of subsequent contraception would be required. After introduction of the new drug, however, circulating quantities of etretinate were detected in patients treated with trans-acitretin. Thus far, re-esterification has been detected in at least 83 cases. The 2-month period of strict contraception initially recommended after oral intake of trans-acitretin has been extended to 2 years, as with etretinate. We review some aspects of trans-acitretin metabolism, with special emphasis on etretinate formation. Re-esterification of trans-acitretin into etretinate takes place under varying conditions in volunteers and patients, as well as in animal models. Ethanol is a co-factor for the enzymatic re-esterification of trans-acitretin. It is unclear whether the introduction of trans-acitretin has been of any significant benefit to patients. Monitoring of plasma retinoid levels during and after retinoid therapy remains of decisive importance in managing difficult cases and or in approving decisions for pregnancy.

Kinetics of drug delivery to the arterial wall via polyurethane-coated removable nitinol stent: comparative study of two drugs.

Polymer-coated removable stents were used to deliver 14C-labeled etretinate and 3H-labeled forskolin to the vessel wall in 31 New Zealand White rabbits to study their kinetics. Stents loaded with etretinate (n = 8) and forskolin (n = 14) were implanted in the rabbit carotid arteries, and the animals were euthanized at different time intervals. Drug levels were measured in the media and adventitia of the stented segment, in distant tissues, and in blood. In four rabbits, forskolin-loaded stents were percutaneously retrieved 2 hr after implantation in the carotid artery, and the tissue and blood levels were determined 2 and 24 hr after retrieval. In seven rabbits etretinate-loaded stents were retrieved 72 hr after implantation in abdominal aorta, and drug levels were measured in the tissues and blood immediately after and at 1 and 4 days after retrieval. Levels of etretinate in the vessel wall peaked at 24 hr (250 ng/mg) and remained high up to 72 hr (185 ng/mg) after stent placement. Levels of forskolin peaked within 2 hr of stent placement (135 ng/mg) and rapidly declined to 4.9 ng/mg at 24 hr with the stent in situ. About 50% (1.4 mg) of the original etretinate remained in the stent at 72 hr compared to about 5% (0.08 mg) of forskolin at 24 hr. Ratio of peak drug levels in the vessel wall to those in the blood was 6,000 for etretinate and 780 for forskolin. (ABSTRACT TRUNCATED AT 250 WORDS)

Inability to detect plasma etretinate and acitretin is a poor predictor of the absence of these teratogens in tissue after stopping acitretin treatment.

1. Concentrations of etretinate, acitretin and its main metabolite 13-cis-acitretin were measured in plasma and subcutaneous fat samples from 37 women of childbearing age exposed to acitretin before November 1990. Twenty of the women still used acitretin and 17 had stopped therapy for a period ranging from 1 to 29 months. 2. The prevalences of detectable etretinate concentrations were 45% and 83% in plasma and subcutaneous tissue, respectively, among current acitretin users and 18% and 86% among those who had stopped acitretin therapy. Thus, inability to detect plasma etretinate is a poor predictor of the absence of etretinate in fat. 3. Acitretin and/or etretinate were detectable in fat and in some cases in plasma from women who had ceased acitretin therapy for up to 29 months. 4. We suggest that (cis)-acitretin and etretinate should be monitored in subcutaneous tissue when plasma measurements are negative. The recommended contraception period of 2 years after cessation of acitretin therapy should be reconsidered to avoid the risk of teratogenicity.

Kinetics of tissue distribution and elimination of retinoid drugs in the rat. II. Etretinate.

Rats were injected with single intravenous doses of etretinate (6 mg/kg), and concentrations of the drug and its metabolites, acitretin and 13-cis-acitretin, were determined in plasma and nine tissues up to 96 hr. A newly developed sensitive method for the determination by HPLC of the three retinoids in tissues was used. Etretinate rapidly appeared in most tissues and underwent a redistribution from highly perfused organs into muscle, skin, and ultimately, adipose tissue. Tissue/plasma concentration ratios ranged from 14 to 1, with the highest value in adipose tissue. In this tissue, maximum concentration was reached after 1.5 hr and remained practically constant up to 96 hr. Etretinate was rapidly hydrolyzed to form acitretin at concentrations that surpassed those of the parent drug in plasma, liver, kidney, and brain. After 6 hr, approximately 45% of etretinate had been metabolized to acitretin and approximately 40% to unidentified metabolites. These metabolites were not observed in tissues after 6 hr postdose. The parent drug was not observed 12 hr postdose, except for 6% of the dose remaining in adipose tissue. Etretinate elimination, in most tissues, was biphasic with terminal half-lives of 41 hr in skin, 1-6 hr in other lean tissues, and 1.7 hr in plasma. A volume of distribution of 1.7 liters/kg was determined, and a clearance of 12 ml.min-1.kg-1. Etretinate is characterized by rapid metabolism, transient storage in skin, and prolonged storage at a low level in adipose tissue as a deep compartment. A comparison of the pharmacokinetics of the closely related retinoids, etretinate and acitretin, disclose very pronounced differences.

Teratogenic risk with etretinate and acitretin treatment.

Etretinate (Tigason, Tegison) and its active metabolite acitretin (Neotigason, Soriatane) are known teratogens. Pregnancy should be avoided during treatment and until 2 years after treatment discontinuation. The question is discussed whether a dose or a blood concentration of the drug below which there is no teratogenic risk can be determined. Animal experimental and human pharmacokinetic data are reviewed. An evaluation of the outcomes of pregnancies which occurred in mothers exposed to etretinate or acitretin was performed. A threshold dose in human therapy below which there is no risk of congenital malformation cannot be determined based on animal experimental data. With regard to pharmacokinetics, there are currently no data suggesting that blood levels of the drug below the detection limit of 2 ng/ml are associated with a teratogenic risk. The most useful information is given by reports in women who were exposed to either retinoid before or during pregnancy. The data indicate that the risk of spontaneous abortion or congenital malformation is high when the drug is administered during the first trimester of pregnancy. After treatment discontinuation, the risk is low since the number of abnormalities seems not to exceed those observed in a general population. There are currently no available data which suggest that the pregnancy warnings are inappropriate in terms of duration of contraception.

In vivo skin penetration of acitretin in volunteers using three sampling techniques.

Etretinate and acitretin are given orally to treat psoriasis and various keratinization disorders. Acitretin, the main active metabolite of etretinate, has the pharmacokinetic advantage of being rapidly eliminated, but it shares etretinate's toxicologic profile. Thus a topical delivery of acitretin with no or reduced systemic adverse effects is desirable. To characterize the therapeutic potential of topically delivered acitretin, we quantitatively assessed its percutaneous penetration in healthy human volunteers. Additionally, three skin sampling techniques, the punch biopsy, the shave biopsy, and the suction blister technique, were validated to quantitate acitretin in the skin. The results suggest that topical delivery of acitretin renders skin concentrations which exceed those reported after oral administration of etretinate or acitretin. However, because of possible interlaminate drug contamination, drug localization within a particular skin compartment cannot be determined.

Pharmacokinetics and drug interactions of etretinate and acitretin.

Acitretin, the metabolite of etretinate, is eliminated far more rapidly from the human body than is etretinate. It had therefore been suggested that only a short period of contraception would be required after the cessation of long-term therapy with acitretin. However, recent studies have demonstrated the presence of etretinate in the plasma of patients who were treated with acitretin. In this article we provide results from a study in our center and discuss earlier data in light of the recently discovered metabolic pathways for acitretin. Reesterification of acitretin to etretinate, however, results in a loss of the metabolic advantages of acitretin. Because of this situation the recommended contraception period after acitretin therapy has been lengthened to 2 years.

Systemic pharmacokinetics of acitretin, etretinate, isotretinoin, and acetylenic retinoids in guinea pigs and obese rats.

Etretinate, a highly lipophilic retinoid, is known to accumulate in the human body with a slow systemic elimination (half-life approximately 100 days) after long-term treatment. Retinoids with high lipophilicity and slow body elimination have the propensity of eliciting teratogenic effects. Therefore, synthetic retinoids with reduced systemic retention are desired. In this study, we evaluated the systemic pharmacokinetics of acitretin, etretinate, isotretinoin, synthetic acetylenic retinoic acids (AGN 190121, AGN 190186, and AGN 190299), and acetylenic retinoates (AGN 190073, AGN 190089, and AGN 190168) in guinea pigs following iv doses. Their pharmacokinetics were also measured in obese rats to probe the effect of body fat on the drug disposition of retinoids. The acetylenic retinoates were hydrolyzed to their corresponding free acids at a much faster rate than etretinate in both animal species. All retinoates showed faster body clearance and larger volume of distribution than their free acids. In the obese rats, longer elimination half-lives and slower body clearance of the retinoids, except isotretinoin, were observed as compared to those in the normal rats. These results suggest that body fat has a significant effect on drug disposition and slows down the systemic clearance of retinoids. Since the synthetic acetylenic retinoates rapidly converted to their less lipophilic free acids after systemic absorption, the potential accumulation of these retinoids, as reported for lipophilic etretinate, were unlikely to occur in humans and animals.

Etretinate absorption in the in situ perfused intestinal lumen: preliminary studies in the rat.

The absorption characteristics of etretinate were examined in the Sprague-Dawley rat with the use of the in situ intestinal lumen perfusion model. Intestinal segments of 15-50 cm were cannulated and perfused with etretinate solutions of 178-1405 micrograms ml-1 in a single-pass manner at flow rates of 0.15-0.96 ml min-1. The intestinal effluent was collected and analyzed by HPLC for etretinate, as was blood that was drawn from the jugular vein. Despite its lipophilic nature, etretinate does not appear to be well absorbed from the rat intestine; the maximum fraction disappearing from the intestinal lumen was approximately 0.35. The absorption of etretinate appeared to be controlled by the aqueous diffusion layer. There was no evidence that the uptake of etretinate by the gastrointestinal membrane involved an active transport system.

Interaction of etretinate with methotrexate pharmacokinetics in psoriatic patients.

Combined treatment of psoriasis with methotrexate and etretinate may be associated with hepatoxicity. This study investigated the potential effects of steady state etretinate administration on methotrexate pharmacokinetics in six psoriatic patients. When compared with a matched group a significantly higher mean value for the maximum plasma concentration Cmax (992 nmol/L +/- 94 SE vs 721 nmol/L +/- 35 SE) for methotrexate was found (P less than .05) after intramuscular administration of 0.2 mg/kg body weight of the drug. In accordance with this finding mean values of the time (tmax) to reach Cmax, half-life of the absorption (t1/2ka) and the apparent volume of distribution at steady state Vss were also lower than in the control groups but did not deviate significantly. Total clearance differed very little and insignificantly between the two groups. Absorption and disposition rates of etretinate during combined treatment with methotrexate were not significantly altered compared with previous results in psoriatic patients only receiving etretinate. Overall, these results indicate that the apparently increased risk for developing hepatotoxic reactions during coadministration of methotrexate and etretinate cannot be explained by drug accumulation due to pharmacokinetic interaction. A possible influence on potential hepatotoxicity of an increase of Cmax for methotrexate cannot be excluded.

UV-induced isomerization of oral retinoids in vitro and in vivo in hairless mice.

Ultraviolet (UV) irradiation causes isomerization and destruction of many vitamin A analogues (retinoids). Using high-performance liquid chromatography (HPLC), we investigated in vitro and in vivo the effects of UV irradiation on 2 all-trans aromatic retinoids (etretinate and acitretin) and on 13-cis retinoic acid (isotretinoin). When etretinate and acitretin dissolved in ethanol were irradiated with UVB (280-320 nm; 10-336 mJ/cm2) or UVA (320-400 nm; 1-5 J/cm2), extensive and reproducible cis-isomerizations occurred at the 13-position (cis/trans ratio approximately 1.6 in all experiments) but there was no progressive photodegradation of the molecules. Irradiation of isotretinoin produced only moderate trans-isomerization but the sum of HPLC peak heights fell with increasing UV doses, being 72% of the original value after 336 mJ/cm2 of UVB. Hairless mice were given etretinate (50 mg/kg bw), acitretin (200 mg/kg) or isotretinoin (50 mg/kg) on days 1, 4 and 7 and were irradiated daily for 8 d with 13 mJ/cm2 UVB plus 1 J/cm2 UVA. Samples of serum, dorsal skin and liver were collected and retinoids analyzed by HPLC. In the etretinate and acitretin-treated, irradiated animals the serum concentrations of the 13-cis isomers were 2-6 times higher than in nonirradiated controls. Irradiated epidermis also contained significantly higher concentrations of 13-cis etretinate and 13-cis acitretin than did control epidermis. The serum and epidermal concentrations of all-trans etretinate and acitretin were unchanged or even increased after irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Teratogenicity of etretinate during early pregnancy in the rat and its correlation with maternal plasma concentrations of the drug.

Sprague-Dawley female rats were treated with a single oral dose of 0 (vehicle), 10, or 25 mg/kg of etretinate (ET), an aromatic retinoid, on gestation day 6, 7, or 8. While treatment on day 8 with both dosages of ET was highly teratogenic, no evidence of embryotoxicity, considered to be treatment related, was observed when the same doses were administered on day 6 or 7. We concluded that the rat embryo is not susceptible to teratogenic effects of ET on gestation day 6 or 7 and that day 8 is the earliest susceptible period for ET teratogenesis. This may well be true of retinoids as a class since we have observed similar results for all-trans- and 13-cis-retinoic acids (unpublished findings). In another study, mated rats were treated with a single oral dose of ET on day 8. No evidence of embryotoxicity was observed at dosages of 1, 3, and 6 mg/kg; in contrast, treatment with 10, 15, or 25 mg/kg of ET resulted in an increasingly greater number of malformed fetuses and resorptions. Plasma concentrations of ET and three metabolites [acitretin (AC), 13-cis-etretinate (13-cis-ET), and 13-cis-acitretin (13-cis-AC)) were determined in mated rats given a single oral non-teratogenic (3 or 6 mg/kg) or teratogenic (10 or 25 mg/kg) dose of ET on gestation day 8. The AUC0----24hr values of ET and AC, the major metabolite and suspected proximal teratogen, were roughly proportional to the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)