ITMI981079A1 - BILIARY ACIDS AS INDUCERS OF THE CYTOCHROME P450-EMPLOYEE SYSTEM IN PARTICULAR TO ANTI-COLESTATIC ACTIVITY - Google Patents
BILIARY ACIDS AS INDUCERS OF THE CYTOCHROME P450-EMPLOYEE SYSTEM IN PARTICULAR TO ANTI-COLESTATIC ACTIVITY Download PDFInfo
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- ITMI981079A1 ITMI981079A1 ITMI981079A ITMI981079A1 IT MI981079 A1 ITMI981079 A1 IT MI981079A1 IT MI981079 A ITMI981079 A IT MI981079A IT MI981079 A1 ITMI981079 A1 IT MI981079A1
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- Prior art keywords
- acid
- alpha
- use according
- beta
- bile acids
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Description
DESCRIZIONE DESCRIPTION
La presente invenzione si riferisce ad acidi biliari come induttori del sistema citocromo P450-dipendente, particolarmente utili per il trattamento di patologie indotte da colestasi. The present invention relates to bile acids as inducers of the cytochrome P450-dependent system, particularly useful for the treatment of pathologies induced by cholestasis.
In particolare, la presente invenzione si riferisce all'utilizzo di acidi biliari e composti analoghi per eliminare e prevenire il danno epatico indotto da acidi biliari lipofili e tossici e da altra tossine in genere . In particular, the present invention relates to the use of bile acids and similar compounds to eliminate and prevent hepatic damage induced by lipophilic and toxic bile acids and by other toxins in general.
E' noto che gli acidi biliari hanno trovato inizialmente utilizzo nella terapia litolitica in funzione della loro capacità di desaturare la bile del colesterolo, mentre successivamente sono stati utilizzati nella terapia delle epatopatie croniche. It is known that bile acids initially found use in litholytic therapy due to their ability to desaturate cholesterol bile, while subsequently they were used in the treatment of chronic liver diseases.
Tra questi, l'acido chenodesossicolico (CDCA) è stato il primo a trovare un utilizzo nella clinica. Tuttavia, la somministrazione di questo acido, poiché induce una ipertransaminasemia transitoria e reversibile nel 30% dei soggetti trattati a scopo litolitico, ne ha suggerito la potenziale tossicità epatica. Among them, chenodeoxycholic acid (CDCA) was the first to find use in the clinic. However, the administration of this acid, since it induces a transient and reversible hypertransaminasemia in 30% of subjects treated for litholytic purposes, has suggested its potential hepatic toxicity.
Questi inconvenienti sono stati superati cn l'avvento del 7 beta epimero del CDCA, l'acido ursodesossicolico {UDCA) il cui utilizzo nella te rapia litolitica si è dimostrato pressoché privo di effetti collaterali a livello epatico. Questo fatto ha consentito di estendere l’utilizzo dell'UDCA a scopo litico anche nei pazienti epatopatici cronici. These drawbacks have been overcome with the advent of the 7 beta epimer of CDCA, ursodeoxycholic acid (UDCA), whose use in litholytic therapy has proven to be practically free of side effects in the liver. This fact has made it possible to extend the use of UDCA for lytic purposes even in chronic liver disease patients.
Risale al 1985 la constatazione che la somministrazione di UDCA in sei pazienti con epatite cronica attiva ed affetti da calcolosi biliare, abbia indotto una consistente riduzione dei livelli serici delle transaminasi. Si è quindi postulato che la ritenzione e l aumentata perfusione epatica con acidi biliari endogeni, detergenti e quindi potenzialmente epatotossici , come il CDCA e l'acido desossicolico, possano giocare un ruolo importante nella patogenesi delle epatopatie croniche colestatiche. It dates back to 1985 that the administration of UDCA in six patients with chronic active hepatitis and suffering from gallstones induced a consistent reduction in the serum levels of transaminases. It has therefore been postulated that retention and increased hepatic perfusion with endogenous, detergent and therefore potentially hepatotoxic bile acids, such as CDCA and deoxycholic acid, may play an important role in the pathogenesis of chronic cholestatic liver diseases.
Al contrario, si è pensato che la somministrazione di UDCA esogeno, determinando l'arricchimento del pool complessivo con un acido biliare idrofilico e meno detergente a spese degli acidi biliari endogeni, possa determinare un'azione protettiva sull'epatocita. On the contrary, it has been thought that the administration of exogenous UDCA, determining the enrichment of the overall pool with a hydrophilic and less detergent bile acid at the expense of the endogenous bile acids, can determine a protective action on the hepatocyte.
Alla luce di queste considerazioni sono stati effettuati svariati studi atti ad evidenziare un miglioramento degli indici bioumorali nei pazienti epatopatici cronici trattati con UDCA. In light of these considerations, several studies have been carried out aimed at highlighting an improvement in biohumoral indices in chronic liver disease patients treated with UDCA.
Recentemente la comunità scientifica ha quindi proposto una serie di ipotesi sui meccanismi di azione mediante il quale l'UDCA determina un miglioramento degli indici di necrosi e di colestasi. Fra queste le più accreditate inducono a pensare: Recently, the scientific community has therefore proposed a series of hypotheses on the mechanisms of action by which UDCA determines an improvement in the indices of necrosis and cholestasis. Among these the most accredited lead us to think:
- un effetto stabilizzante sulle membrane cellulari, con riduzione della loro permeabilità, - a stabilizing effect on cell membranes, with a reduction in their permeability,
- un effetto antagonista nei confronti dell'aumentata sintesi della fosfatasi alcalina conseguente alla ritenzione di acidi biliari endogeni in corso di colestasi, - an antagonistic effect against the increased synthesis of alkaline phosphatase resulting from the retention of endogenous bile acids in the course of cholestasis,
- un'azione favorente l’escrezione degli enzimi epatici nella bile, dovuta ad un diminuito rientro degli enzimi dalla bile nel sangue sinusoidale in funzione di un effetto protettivo esercitato dall'UDCA sulle giunzioni serrate (tight junctions) canalicolari o ad un vero e proprio effetto coleretico associato ad una aumentata secrezione di bicarbonati. - an action favoring the excretion of hepatic enzymes in the bile, due to a decreased return of the enzymes from the bile into the sinusoidal blood as a function of a protective effect exerted by the UDCA on the canalicular tight junctions or to a real choleretic effect associated with an increased secretion of bicarbonates.
Studi sperimentali hanno inoltre evidenziato che, in ratti con legamento del coledoco, si realizza una riduzione dei livelli di citocromo £>450 microsomiale e che in vitro gli acidi biliari producono una generale riduzione dell'attività catalitica del citocromo P450 e degli altri enzimi epatici microsomiali. Experimental studies have also shown that, in rats with choledochus ligament, there is a reduction in the levels of cytochrome ≤> 450 microsomal and that in vitro the bile acids produce a general reduction of the catalytic activity of cytochrome P450 and other microsomal liver enzymes. .
Allo stato attuale è quindi risaputo che gli acidi biliari sono inibitori di tali attività che sono indice di una tossicità epatica in casi di epatopatie croniche con colestasi, laddove si realizzano alte concentrazioni intraepatiche di acidi biliari endogeni. Questo fatto si verifica in altre patologie intestinali in cui, per effetto di un'alterazione nella microflora intestinale, si riscontra una produzione di acidi biliari secondari più lipofili ed epatotossici. At present, it is therefore known that bile acids are inhibitors of these activities which indicate liver toxicity in cases of chronic liver disease with cholestasis, where high intrahepatic concentrations of endogenous bile acids occur. This fact occurs in other intestinal pathologies in which, due to an alteration in the intestinal microflora, there is a production of more lipophilic and hepatotoxic secondary bile acids.
Uno scopo generale della presente invenzione consiste nel fornire nuovi utilizzi in campo terapeutico per selezionati acidi biliari. A general object of the present invention is to provide new uses in the therapeutic field for selected bile acids.
Uno degli scopi precipui della presente invenzione consiste nel provvedere nuovi farmaci o medicamenti ad attività anticolestatica la cui somministrazione comporti limitati effetti collaterali sistemici. One of the main purposes of the present invention is to provide new drugs or medicaments with anticolestatic activity the administration of which involves limited systemic side effects.
Un ulteriore scopo della presente invenzione consiste nel provvedere farmaci per il trattamento delle malattie epatiche sia di tipo A further object of the present invention is to provide drugs for the treatment of both type and hepatic diseases
vo che di tipo indotto da sostanze tossiche esogene che siano facilmente reperibili sul mercato a costi competitivi. type induced by exogenous toxic substances that are easily available on the market at competitive costs.
Non ultimo scopo consiste nel provvedere medicamenti che siano in grado di prevenire il danno indotto da acidi biliari lipofili e tossici ed altre tossine utilizzabili sia nel trattamento di esseri umani che di animali. Not least object is to provide medicaments which are capable of preventing the damage induced by lipophilic and toxic bile acids and other toxins which can be used both in the treatment of human beings and animals.
Alla luce di questi scopi e di altri ancora che appariranno più evidenti in seguito, viene fornito, in accordo con la presente invenzione, l'uso di acidi biliari di formula (I): In the light of these purposes and of others still which will become more evident in the following, the use of bile acids of formula (I) is provided in accordance with the present invention:
in cui in which
R^ è H, RgCOO in cui è un alchile con da 1 a 6 atomi di C, RgCOO<” >in cui Rg è alchile con da 1 a 6 atomi di C, ed i loro sali farmaceuticamente accettabili, per la produzione di un medicamento per indurre il sistema citocromo P4S0-glicoproteina-P. In particolare detti acidi biliari di formula (I) ed i loro sali farmaceuticamente accettabili sono utili per la produzione di un medicamento per la prevenzione od il trattamento delle patologie indotte o associate a colestasi. R ^ is H, RgCOO wherein it is an alkyl with from 1 to 6 C atoms, RgCOO <"> in which Rg is alkyl with from 1 to 6 C atoms, and their pharmaceutically acceptable salts, for the production of a medicament to induce the cytochrome P4S0-P-glycoprotein system. In particular, said bile acids of formula (I) and their pharmaceutically acceptable salts are useful for the production of a medicament for the prevention or treatment of pathologies induced or associated with cholestasis.
Tra gli acidi biliari di formula (I) sono preferiti quelli in cui è scelto tra H, -CHjCOO , sali con metalli alcalini. Among the bile acids of formula (I) those in which it is selected from H, -CHjCOO, salts with alkali metals are preferred.
Nell'ambito della presente invenzione, con il termine patologie indotte o associate a colestasi si intendono malattie sia in campo medico che veterinario, comprendenti la cirrosi biliare primitiva, l epatopatie croniche colestatiche, l'epatopatie infantili associate, o meno, a fibrosi cistica, l'epatopatie indotte da tossine di varia natura, incluso farmaci, tossici ambientali, sostanze endogene. Sono altresì ricomprese, nell'ambito delle patologie associate a colestasi, le malattie intestinali. Within the scope of the present invention, the term pathologies induced or associated with cholestasis means diseases both in the medical and veterinary field, including primary biliary cirrhosis, chronic cholestatic liver disease, infantile liver disease associated, or not, with cystic fibrosis, liver disease induced by toxins of various kinds, including drugs, environmental toxicants, endogenous substances. Intestinal diseases are also included in the pathologies associated with cholestasis.
Nell utilizzo profilattico o terapeutico come molecole/agenti ad attività anticolestatica, gli acidi biliari di formula (I) dell'invenzione, sono somministrati in un quantitativo preferibilmente compreso tra 5 e 20 mg/kg corporeo, attraverso una singola o multipla somministrazione giornaliera. In prophylactic or therapeutic use as molecules / agents with anticolestatic activity, the bile acids of formula (I) of the invention are administered in a quantity preferably between 5 and 20 mg / kg body, through a single or multiple daily administration.
I dosaggi specifici varieranno secondo le necessità del soggetto da trattare, la gravità della patologia in atto e l'attività del composto utilizzato. La determinazione del dosaggio ottimale da somministrare in ciascuna particolare situazione rientra nell'ambito delle possibilità di scelta del medico. The specific dosages will vary according to the needs of the subject to be treated, the severity of the disease in progress and the activity of the compound used. Determining the optimal dosage to administer in each particular situation is within the physician's choice.
Nella produzione di un medicamento comprendente un acido biliare di formula <(>I<) >secondo l'invenzione, vengono utilizzati veicoli farmaceuticamente accettabili, sia in forma liquida che solida. In the production of a medicament comprising a bile acid of formula <(> I <)> according to the invention, pharmaceutically acceptable carriers are used, both in liquid and solid form.
Le<' >preparazioni solide includono compresse, capsule, boli di tipo veterinario, cachets e polveri. Solid preparations include tablets, capsules, veterinary-type boluses, cachets and powders.
Veicoli farmaceuticamente accettabili includono una o più eccipienti, diluenti, agenti disperdenti e solubilizzanti, lubrificanti, leganti a disaggreganti e sostanze per il rilascio protratto del principio attivo. Pharmaceutically acceptable carriers include one or more excipients, diluents, dispersing and solubilizing agents, lubricants, disaggregating binders and substances for sustained release of the active ingredient.
Nella realizzazione di compresse, l'acido biliare di formula (I) è in miscela con uno o più veicoli, in proporzioni idonee e in forma compattata e sagomata. In the production of tablets, the bile acid of formula (I) is in admixture with one or more vehicles, in suitable proportions and in a compacted and shaped form.
A titolo di esempio i medicamenti e le formulazioni farmaceutiche prodotte in accordo con l'invenzione contengono dal 5 al 30% in peso di almeno un acido biliare di formula .(I). By way of example, the medicaments and pharmaceutical formulations produced in accordance with the invention contain from 5 to 30% by weight of at least one bile acid of formula (I).
Veicoli idonei nella preparazione di medicamenti ad attività anticolestatica comprendono carbonato di magnesio, stearato di magnesio, talco, lattosio, amido di mais, saccarosio, pectina, destrina, metilcellulosa, carbossimetilcellulosa di sodio, burro di cacao, cere bassofondenti e simili. Suitable vehicles in the preparation of anti-cholestatic medicaments include magnesium carbonate, magnesium stearate, talc, lactose, corn starch, sucrose, pectin, dextrin, methylcellulose, sodium carboxymethylcellulose, cocoa butter, low melting waxes and the like.
Tra le forme farmaceutiche realizzabili mediante l'uso degli acidi biliari di formula (I) sono comprese le forme a pronto rilascio e le forme a rilascio ritardato o controllato. Among the pharmaceutical forms which can be produced by using the bile acids of formula (I) are included the ready-release forms and the delayed or controlled release forms.
Le preparazioni in forma liquida includono soluzioni adatte per la somministrazione parenterale ed orale. The liquid form preparations include solutions suitable for parenteral and oral administration.
Le forme ad uso parenterale sono vantaggiosamente in forma di soluzioni acquose sterili e possono includere ulteriori solventi come etanolo, glicole propilenico. The forms for parenteral use are advantageously in the form of sterile aqueous solutions and can include further solvents such as ethanol, propylene glycol.
La somministrazione dei medicamenti dell'invenzione viene vantaggiosamente effettuata nell'uomo prima dei pasti (30-60 minuti prima) per consentire che si realizzi l'induzione del meccanismo P450 dipendente e che predisponga il fegato a rimuovere in breve tempo il bolo di acidi biliari endogeni che per effetto del pasto vengono rimossi dalla colecisti, rilasciati nell'intestino, assorbiti e, attraverso la vena porta pervengono al fegato. The administration of the medicaments of the invention is advantageously carried out in humans before meals (30-60 minutes before) to allow the induction of the P450 dependent mechanism to take place and to predispose the liver to remove the bile acid bolus in a short time. endogenous which as a result of the meal are removed from the gallbladder, released in the intestine, absorbed and, through the portal vein, reach the liver.
In tali condizioni l'induzione del sistema P450-glicoproteina-P facilita il trasporto e l'escrezione di acidi biliari potenzialmente tossici che si accumulano nel fegato. Under these conditions, induction of the P450-P-glycoprotein system facilitates the transport and excretion of potentially toxic bile acids that accumulate in the liver.
La somministrazione degli acidi biliari di formula (I) induce l'attività del citocromo P450 a cui è associata l'indùzione della glicoproteina P, una speciale pompa ATP-dipendente, di natura proteica presente in numerosi tessuti con la funzione di eliminare dalle cellule sostanze citotossiche. A questa induzione del sistema citocromo P450-glicoproteina-P è strettamente associata la capacità da parte di queste molecole, di prevenire o minimizzare il danno indotto dalla successiva somministrazione di acidi biliari lipofili e tossici, quali, ad esempio, l'acido chenodesossicolico e desossicolico sia nelle forme libere che coniugate con glieina e taurina che vengono rapidamente escrete dal fegato con un valore di trasporto massimo aumentato di almeno 10 volte, tramite l'induzione della pompa di asporto (glicoproteina P). The administration of bile acids of formula (I) induces the activity of cytochrome P450 which is associated with the induction of the P-glycoprotein, a special ATP-dependent pump, of a protein nature present in numerous tissues with the function of eliminating substances from the cells cytotoxic. This induction of the cytochrome P450-glycoprotein-P system is closely associated with the ability of these molecules to prevent or minimize the damage induced by the subsequent administration of lipophilic and toxic bile acids, such as, for example, chenodeoxycholic and deoxycholic acid. both in the free and conjugated forms with gliein and taurine which are rapidly excreted by the liver with a maximum transport value increased by at least 10 times, through the induction of the removal pump (P-glycoprotein).
In accordo ad una forma di realizzazione particolarmente preferita della presente invenzione detti acidi biliari sono scelti dal gruppo riportato nel seguente schema I, tra questi, l'acido ursodesossicolico e/o l'acido tauroiodesossicolico essendo particolarmente preferiti. According to a particularly preferred embodiment of the present invention, said bile acids are selected from the group reported in the following scheme I, among these, ursodeoxycholic acid and / or tauroiodesoxycholic acid being particularly preferred.
Schema I Scheme I
Si è verificato che gli acidi biliari di formula (I) presentano una lipofilia e detergenza inferiori a quella di acidi biliari endogeni con valori di log P inferiori e concentrazioni micellari critiche più elevata, come risulta dalla seguente Tabella 1. It has been verified that the bile acids of formula (I) have a lipophilicity and detergency lower than that of endogenous bile acids with lower log P values and higher critical micellar concentrations, as shown in the following Table 1.
Tabella 1 : proprietà cnimica-fisiche degli acidi biliari studiati. Table 1: chemical-physical properties of the bile acids studied.
E' stato verificato che gli acidi biliari di formula (I) secondo l'invenzione, inducono, sia nel topo che nel ratto, il sistema monoossigenasico citocromo P450-dipendente, con particolare riferimento alle isoforme P450 3A cui è specificatamente associata l’induzione della glicoproteina P. It has been verified that the bile acids of formula (I) according to the invention induce, in both mice and rats, the cytochrome P450-dependent monooxygenase system, with particular reference to the isoforms P450 3A which is specifically associated with the induction of glycoprotein P.
Secondo un altro aspetto la presente invenzione si riferisce all'utilizzo di un principio attivo farmacologico in grado di indurre il sistema citocromo P450/glicoproteina P per la preparazione di un medicamento per il trattamento di epatopatie e/o malattie intestinali. According to another aspect, the present invention relates to the use of a pharmacological active principle capable of inducing the cytochrome P450 / P-glycoprotein system for the preparation of a medicament for the treatment of liver and / or intestinal diseases.
Detti principi attivi sono vantaggiosamente scelti tra derivati glucocorticoìdi quali dexametasone, betametasòne, 9alfa-fluoroìdrocortisone, alfa-metilprednisolone , triamcinolone acetonide, fluocinolone acetonide, triamcinolone, llbeta-idrossiprogesterone, prednisolone, corticosterone, idrocortisone; derivati del pregnenolone 16alfa-carbonitrile quali lSalfametil-16,17-epossi-pregnenolone , 16 alfa metilpregnolone, deidropregnolone; estrogeni quali beta-estradiolo, progesterone; derivati del testosterone quale alfa metiltestosterone, corticosteroidi quale aldosterone spironolattone, barbiturici, macrolidi, imidazoli, antibiotici quali rifampicina, reserpina, fenobarbitale, verapamil,· midazolam, repamicina, clotrimazolo, FK506, isosafrolo, amiodarone, triactiloleandomicina,-eritromicina, dexametasone, nifedipina, fenitoina e loro miscele. Said active ingredients are advantageously selected from glucocorticoid derivatives such as dexamethasone, betamethasone, 9alpha-fluorohydrocortisone, alpha-methylprednisolone, triamcinolone acetonide, fluocinolone acetonide, triamcinolone, llbeta-hydroxyprogesterone, prednisolone, corticone, hydrogen peroxide; derivatives of pregnenolone 16alpha-carbonitrile such as salfamethyl-16,17-epoxy-pregnenolone, 16 alpha methylpregnolone, dehydropregnolone; estrogens such as beta-estradiol, progesterone; testosterone derivatives such as alpha methyltestosterone, corticosteroids such as aldosterone spironolactone, barbiturates, macrolides, imidazoles, antibiotics such as rifampicin, reserpine, phenobarbital, verapamil, midazolam, repamycin, clotrimazole, FK506, isosaphrole, amiodolycin, dedomycin, dedomycin, dedomycetil phenytoin and their mixtures.
I seguenti esempi vengono forniti a solo scopo illustrativo della presente invenzione e non devono essere intesi in senso limitativo dell'ambito della presente invenzione, come risulta definito dalle accluse rivendicazioni. The following examples are provided for illustrative purposes only of the present invention and are not to be construed as limiting the scope of the present invention, as defined by the attached claims.
ESEMPIO 1 EXAMPLE 1
Sono stati infusi ratti maschi Spague Dawley del peso di ca. 300+/-20 g per via endovenosa con un acido biliare tossico (TCDCA) alla dose di 8 μηιοΐ x min<"1 >x Kg<"1 >per un'ora. Una dose equimolare di THDCA, dotato di attività anticolestatica, è stata quindi co-infusa IV. I controlli sono costituiti da ratti trattati solo con soluzione salina e con solo acido biliare tossico o terapeutico come riportato in Tabella 1. Il modello animale prevede ratti con fistola biliare esterna per la raccolta della bile per ulteriori due ore dall'inizio dell'esperimento e per l'analisi delle molteplici attività enzimatiche del P45Q nel fegato asportato al termine dell'esperimento. Il testosterone, per la capacità di essere metabolizzato in maniera stereo e regio selettiva dalle differenti isoforme del citocromo P450, è stato utilizzato come multi substrato marker delle diverse isoforme stesse. Male Spague Dawley rats weighing approx. 300 +/- 20 g intravenously with a toxic bile acid (TCDCA) at a dose of 8 μηιοΐ x min <"1> x Kg <" 1> for one hour. An equimolar dose of THDCA, endowed with anticolestatic activity, was then co-infused IV. Controls consist of rats treated only with saline solution and with only toxic or therapeutic bile acid as reported in Table 1. The animal model envisages rats with external biliary fistula to collect bile for a further two hours from the start of the experiment and for the analysis of the multiple enzymatic activities of P45Q in the liver removed at the end of the experiment. Testosterone, due to its ability to be metabolized in a stereo and regio selective manner by the different isoforms of cytochrome P450, has been used as a multi-substrate marker of the different isoforms.
Nella seguente Tabella 2, vengono riportati i valori relativi alla In the following Table 2, the values related to the
modulazione del sistema monoossigenasico nel ratto al tempo tQ (basale), modulation of the monooxygenase system in the rat at time tQ (baseline),
t1 (1 ora di infusione) e t2 (2 ore di infusione). Dall'analisi dei dati t1 (1 hour of infusion) and t2 (2 hours of infusion). From data analysis
riportati nella Tabella 2, dove è riportata l'espressione del testosterone reported in Table 2, where the expression of testosterone is reported
idrossilasi in microsomi epatici di animali trattati con TCDCA, si evince hydroxylase in liver microsomes of animals treated with TCDCA, it is inferred
il potente effetto inattivante indotto dall'acido già dopo un'ora di infu¬ the powerful inactivating effect induced by the acid already after an hour of infu¬
sione (la percentuale di calo raggiunge addirittura il 97% per l'attività sion (the percentage of decline reaches as much as 97% for the activity
testosterone 16alfa e 2alfa-idrossilasi) indice dell'elevata tossicità di testosterone 16alpha and 2alpha-hydroxylase) indicating the high toxicity of
questo acido biliare. this bile acid.
Al contrario, il THDCA è stato in grado di determinare un potente e Conversely, THDCA was able to determine a potent e
significativo effetto induttivo a carico del sistema P450 con particolare significant inductive effect on the P450 system with particular
riferimento al citocromo P4503A (testosterone Sbeta e 2beta-idrossilasi). reference to cytochrome P4503A (testosterone Sbeta and 2beta-hydroxylase).
TABELLA 2 - TESTOSTERONE IDROSSILASI IN MICROSOMI EPATICI 01 RATTI TABLE 2 - TESTOSTERONE HYDROXYLASE IN LIVER MICROSOMES 01 RATS
TRATTATI CON TCDCA TREATED WITH TCDCA
ESEMPIO 2 EXAMPLE 2
L'effetto induttivo (Tabella 3) dopo un'ora ha raggiunto incrementi dell'ordine del 28,29% (16alfa-idrossitestosterone) e del 48,42% (2alfaidrossitestosterone) e si è ulteriormente rafforzato con 2 ore di infusione raggiungendo l'incremento limite del 93,38% (2alfaidrossitestosterone). L'attività testosterone 6beta-idrossilasi, associata all'isoforma P450 3A, è quella maggiormente indotta, non in termini percentuali, visto che raggiunge il 29,33%, ma bensì in termini di "potenza catalitica<1>'. Essendo infatti espressa in nmol x mg<"1 >x min<"1>, l'enzima indotto è in grado di metabolizzare ca. 14000 pmol in più nell'unità di tempo per milligrammo di proteina, un valore altamente superiore a quello ottenuto con l'induzione delle altre attività espresse in pmol x mg<"1 >x min<" 1 >riportate nella seguente Tabella 3. The inductive effect (Table 3) after one hour reached increases of the order of 28.29% (16alpha-hydroxytestosterone) and 48.42% (2alphahydroxytestosterone) and was further strengthened with a 2-hour infusion reaching the limit increase of 93.38% (2alphahydroxytestosterone). The testosterone 6beta-hydroxylase activity, associated with the P450 3A isoform, is the most induced, not in percentage terms, as it reaches 29.33%, but rather in terms of "catalytic power <1>". in nmol x mg <"1> x min <" 1>, the induced enzyme is able to metabolize about 14000 pmol more in the unit of time per milligram of protein, a value much higher than that obtained with the induction of the other activities expressed in pmol x mg <"1> x min <" 1> reported in the following Table 3.
TABELLA 3 - TESTOSTERONE IDROSSILASI IN MICROSOMI EPATICI DI RATTI TABLE 3 - TESTOSTERONE HYDROXYLASE IN LIVER MICROSOMES OF RATS
TRATTATI CON TCOCA-THOCA TREATED WITH TCOCA-THOCA
Quando il THDCA è stato co-infuso con l'acido biliare tossico When THDCA was co-infused with toxic bile acid
{TCDCA), sorprendentemente, non viene registrato il precedente drastico e {TCDCA), surprisingly, the drastic precedent e is not recorded
repentino effetto inattivante gli enzimi del metabolismo degli xenobiotici sudden effect inactivating the enzymes of the metabolism of xenobiotics
ma, al contrario, il THDCA è in grado di svolgere un effetto protettivo but, on the contrary, THDCA is capable of carrying out a protective effect
sul fegato dal suddetto effetto epatotossico. on the liver by the aforementioned hepatotoxic effect.
A riprova di questo fatto, tutte le attività associate alla molecola As evidence of this fact, all the activities associated with the molecule
di testosterone sono risultate, sebbene in misura minore rispetto al trat¬ of testosterone were found, albeit to a lesser extent than in trat¬
tamento con solo THDCA, marcatamente indotte dal co-trattamento, come evi¬ tamento with only THDCA, markedly induced by the co-treatment, as evi¬
denziato in Tabella 4. referenced in Table 4.
TABELLA 4 - TESTOSTERONE IDROSSILASI IN MICROSOMI EPATICI DI RATTI TABLE 4 - TESTOSTERONE HYDROXYLASE IN LIVER MICROSOMES OF RATS
TRATTATI CON THDCA TREATED WITH THDCA
ESEMPIO 3 EXAMPLE 3
E' stata utilizzata 1'amminopirina come substrato preferenziale per le isoforme P450 3A. Il quadro biochimico-enzimologico ha confermato: un drastico calo dell'attività ad opera del trattamento con TCDCA, forte effetto induttivo sul citocromo P450 determinato dall'infusione con THDCA ed effetto protettivo {induzione intermedia) previa co-infusione delle due molecole, come evidenziato nella sotto riportata Tabella 5. Aminopyrine was used as the preferential substrate for the P450 3A isoforms. The biochemical-enzymological picture confirmed: a drastic decrease in activity due to the treatment with TCDCA, strong inductive effect on cytochrome P450 caused by the infusion with THDCA and protective effect (intermediate induction) after co-infusion of the two molecules, as highlighted in Table 5 below.
TABELLA 5 -AMINOPIRINA N-DEMETILASIIN MICROSOMI EPATICIDI RATTI TABLE 5 - AMINOPYRINE N-DEMETHYLASE IN HEPATICIC MICROSOMES IN RATS
TRATTATI CON ACIDIBILIARI TREATED WITH ACIDIBILIARIES
ESEMPIO 4 EXAMPLE 4
Uno studio in parallelo è stato eseguito sul topo ceppo Swiss Albino ODI, maschio, g 30 /-3. A parallel study was performed on the mouse Swiss Albino ODI strain, male, 30 / -3 g.
Gli animali sono staci trattati intraperitonealmente (i.p.) con THDCA, UDCA, o TDCA, alla dose di 12,2 o 24,4 mg/Kg ed il sistema monoossigenasico studiato su frazioni subcellulari epatiche (microsomi a 1050000 x g) ottenute 24 h dopo il trattamento. The animals were treated intraperitoneally (i.p.) with THDCA, UDCA, or TDCA, at a dose of 12.2 or 24.4 mg / kg and the monooxygenase system studied on hepatic subcellular fractions (microsomes at 1050000 x g) obtained 24 h after the treatment.
I risultati hanno messo in evidenza la capacità modulatoria del sisterna particolato monoossigenasico epatico da parte di THDCA e UDCA; al contrario il TDCA non induce variazioni di rilievo. The results highlighted the modulatory capacity of the hepatic monooxygenase particulate system by THDCA and UDCA; on the contrary, the TDCA does not induce significant changes.
Nella Tabella 6 qui di seguito, è riportato l'espressione degli enzimi metabolizzanti utilizzando differenti substrati come probes per le differenti isoforme P450. In particolare, è stata utilizzata 1'amminopirina (per le isoforme P450 3A1/2, come riportato in precedenza per il ratto), il para-nitrofenolo (isoforme P4502E1), 1'etossicumarina (mista), la pentossiresorufina (isoforme P4S02B1) , metossiresorufina (isoforme P4501A2) e 1<1 >etossiresorufina (isoforme P4501A1). Infine, è stato dosato il contenuto totale di P450 e la reduttasi (NADPH-dipendente) associata. In Table 6 below, the expression of metabolizing enzymes using different substrates as probes for the different P450 isoforms is reported. In particular, aminopyrine was used (for the P450 3A1 / 2 isoforms, as previously reported for the rat), para-nitrophenol (isoform P4502E1), ethoxycumarin (mixed), pentoxiresoruphine (isoform P4S02B1), methoxyresoruphine (isoforms P4501A2) and 1 <1> ethoxyresoruphine (isoforms P4501A1). Finally, total P450 content and associated (NADPH-dependent) reductase were measured.
TABELLA 6 - EFFETTI DEL THDCA SUL SISTEMA MONOOSSIGENASICO IN TABLE 6 - EFFECTS OF THDCA ON THE MONOOXYGENASE SYSTEM IN
MICROSOM1 MURIMI EPATICI MICROSOM1 HEPATIC WALLS
I dati relativi al THDCA dimostrano un effetto induttivo a carico del P450 totale nonché dell'attività della reduttasi ad esso associata. Tale induzione si rispecchia nelle attività monoossigenasiche correlate con tali componenti, come si evince dal significativo incremento dell'idrossilazione del p-nitrofenolo, dealchilazione della pentossiresorufina, demetilazione della metossiresorufina, ma, soprattutto, dalla demetilazione dell amminopirina (P450 3A). Al contrario,_il trattamento con TDCA non dà luogo a modulazioni sostanziali, essendo alcune di queste statisticamente significative ma biologicamente non di rilievo come evidenziato nella seguente Tabella 7. The data relating to THDCA demonstrate an inductive effect on the total P450 as well as the reductase activity associated with it. This induction is reflected in the monooxygenase activities correlated with these components, as evidenced by the significant increase in the hydroxylation of p-nitrophenol, dealkylation of pentoxiresorufine, demethylation of methoxyresorufine, but, above all, by the demethylation of aminopyrine (P450 3A). On the contrary, TDCA treatment does not give rise to substantial modulations, some of these being statistically significant but biologically not relevant as shown in the following Table 7.
Analogamente al THDCA, l'UDCA era in grado di indurre marcatamente sistema delle ossidasi a funzione mista come risulta dal significativo incremento di tutti i parametri considerati, con particolare riferimento all'attività amminopirina N-demetilasi, probe per le isoforme P450 3A associate all'induzione della glicoproteina P (Tabella 8) . Similarly to THDCA, UDCA was able to markedly induce a mixed function oxidase system as shown by the significant increase in all the parameters considered, with particular reference to the aminopyrine N-demethylase activity, probe for the P450 3A isoforms associated with induction of P-glycoprotein (Table 8).
Al fine di confermare gli effetti degli acidi biliari di formula ø dell'invenzione, sul sistema monoossigenasico, i campioni sono stati saggiati utilizzando il testosterone come multibiomarcatore. Nella Tabella 9 sono riportati i risultati ottenuti con il trattamento con il THDCA: dall'analisi dei risultati si osserva chiaramente un potente effetto induttivo sulle differenti attività esplicate sul testosterone che comprendono l'attività citocromo P450-3A/PgP dipendente (testosterone 6 beta-idrossilasi) . Mentre il TDCA, studiato anche con il testosterone, non .è stato in grado di modulare le correlate attività ossidasiche (Tabella 10), L'UDCA ha prodotto un significativo incremento di tutti i metaboliti del testosterone, incluse le isoforme 3A-dipendenti (6beta-linked) Tabella 11. In order to confirm the effects of the bile acids of formula ø of the invention, on the monooxygenase system, the samples were tested using testosterone as a multibiomarker. Table 9 shows the results obtained with treatment with THDCA: from the analysis of the results, a powerful inductive effect on the different activities carried out on testosterone is clearly observed, which include cytochrome P450-3A / PgP dependent activity (testosterone 6 beta- hydroxylase). While TDCA, also studied with testosterone, was unable to modulate the related oxidase activities (Table 10), UDCA produced a significant increase in all testosterone metabolites, including 3A-dependent isoforms (6beta). -linked) Table 11.
TABELLA 10 - TESTOSTERONE IDROSSILASI IN MICROSOMl EPATICI DI TOPI TABLE 10 - TESTOSTERONE HYDROXYLASE IN LIVER MICROSOML OF MICE
TRATTATI CON TDCA TREATED WITH TDCA
TABELLA 11 - TESTOSTERONE IDROSSILASI IN MICROSOMl EPATICI DI TOPI TABLE 11 - TESTOSTERONE HYDROXYLASE IN LIVER MICROSOML OF MICE
TRATTATI CON UDCA TREATED WITH UDCA
ESEMPIO 6 EXAMPLE 6
Ratti maschi sono stati pre-infusi (IV) per 30 minuti con un acido biliare di formula (I) secondo l'invenzione, avente proprietà induttive (THDCA) e successivamente infusi con un acido biliare avente proprietà tossiche (TCDCA) a dosi equimolari (8 μτηοΐ x min<-1 >x Kg<"1>, in presenza di, o, in assenza di vinblastina, un noto inibitore della pompa di asporto (glicoproteina P), somministrata (IV) alla dose di 2 /ittioli assolute in un unico bolo. Male rats were pre-infused (IV) for 30 minutes with a bile acid of formula (I) according to the invention, having inductive properties (THDCA) and subsequently infused with a bile acid having toxic properties (TCDCA) at equimolar doses ( 8 μτηοΐ x min <-1> x Kg <"1>, in the presence of, or, in the absence of vinblastine, a known inhibitor of the take-away pump (glycoprotein P), administered (IV) at a dose of 2 / absolute ichthyols in a single bolus.
I risultati, riportati nella Tabella 12 indicano una generalizzata induzione del macchinario P4SO-dipendente nei ratti sottoposti a protezione (ovvero ritenenti THDCA e TCDCA) rispetto al controllo. Al contrario, si osserva una significativa riduzione (circa 30%) dell'attività testosterone 6beta e 2beta-idrossilasi (associata al complesso P450-glicoproteina-P) nel gruppo ricevente l inibitore. Si ritiene che nonostante la presenza di una elevata induzione del P450, la presenza di vinblastina, inibendo la. pompa di asporto ATP-dipendente, mantiene, all'interno della cellula, una quantità di TCDCA sufficiente da inattivare, almeno parzialmente, il sistema monossigenasico tale da ridurre significativamente l'effetto induttivo registrato. The results, reported in Table 12, indicate a generalized induction of the P4SO-dependent machinery in rats subjected to protection (i.e. retentive THDCA and TCDCA) with respect to the control. Conversely, a significant reduction (approximately 30%) of testosterone 6beta and 2beta-hydroxylase activity (associated with the P450-glycoprotein-P complex) is observed in the inhibitor-receiving group. It is believed that despite the presence of a high induction of P450, the presence of vinblastine, inhibiting the. ATP-dependent removal pump, it maintains, inside the cell, a quantity of TCDCA sufficient to inactivate, at least partially, the monooxygenase system such as to significantly reduce the inductive effect recorded.
TABELLA 12- TESTOSTERONE lOROSSILASI IN MICROSOMÌ EPATICI Ol RATTO TABLE 12 - LOROXYLASE TESTOSTERONE IN HEPATIC MICROSOMIES Ol RAT
TRATTATO CON TCDCA-THDCA IN PRESENZA O ASSENZA DI VIN8LAST1NA TREATED WITH TCDCA-THDCA IN THE PRESENCE OR ABSENCE OF VIN8LAST1NA
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