Experimental studies on pharmacology, metabolism and toxicology with tiadenol-disulfoxide. Dissociation of lipid lowering effects and the induction of peroxisomal and microsomal drug-metabolizing enzymes.
The hypolipidemic activity of tiadenol-disulfoxide, the major metabolite of 1,10-bis(hydroxyethylthio)decane (tiadenol, Eulip) in man and in the rat was assessed in various experimental models versus the corresponding activity of tiadenol. Tiadenol-disulfoxide in the normolipidemic rats lowers total serum cholesterol and serum and liver triglycerides in an extent comparable to that of the reference compound. Likewise, it is equally effective as tiadenol in preventing Triton-induced hyperlipidemia and Nath diet induced hypercholesterolemia; in addition tiadenol-disulfoxide is slightly more effective than tiadenol in increasing HDL-cholesterol in hypercholesterolemic rats. At hypolipidemic doses the compound causes no hepatomegaly, no induction of peroxisomal catalase and palmitoyl-CoA oxidase activities, no smooth endoplasmic reticulum proliferation and no induction of microsomal cytochrome P-450 and of cytochrome P-450 dependent enzyme activities: aminopyrine (aminophenazone) N-demethylase, aniline hydroxylase, zoxazolamine hydroxylase and hexobarbital oxidase. At the suprapharmacological dose of 300 mg/kg tiadenol-disulfoxide, if compared to the reference compound, shows a generally lower order of toxicity on these hepatic parameters. Orally administered tiadenol-disulfoxide is well absorbed by the gastrointestinal tract and is eliminated in urine at 45% of the dose in unchanged form, and the remaining being: glucuron-conjugated tiadenol-disulfoxide (10%), S-oxidized metabolites (15%) and sulfoxidized carboxylic metabolites (15%). The compound is well tolerated both in mice and rats. The results of this comparative study demonstrate that: 1. tiadenol-disulfoxide is a substance with promising hypolipidemic properties; 2. tiadenol-disulfoxide is largely responsible for the hypolipidemic activity of tiadenol; 3. hepatomegaly consequent to tiadenol administration is the consequence of the response of the liver cell to the increased functional demand of the mixed function oxidase (MFO) system involved in the metabolism of the drug; 4. peroxisomal enzyme activities induction observed with both drugs at non-pharmacological doses does not play any role in their hypolipidemic action and is not associated with hepatomegaly.
Maffei Facino
R
R
Istituto Chimico Farmaceutico e Tossicologico, Italy.
Carini
M
M
Tofanetti
O
O
Casciarri
I
I
Longoni
E
E
D000818:Animals; D001711:Biotransformation; D002791:Cholesterol, Dietary / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005233:Fatty Alcohols / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005243:Feces / Q000032:analysis; D005260:Female; D006949:Hyperlipidemias / Q000097:blood; D000960:Hypolipidemic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008830:Microbodies / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013454:Sulfoxides / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
D002791:Cholesterol, Dietary; D005233:Fatty Alcohols; D000960:Hypolipidemic Agents; D013454:Sulfoxides; C004568:tiadenol; C053736:tiadenol disulfoxide; D006899:Mixed Function Oxygenases