Comparative Effects of Ursodeoxycholic Acid and Chenodeoxycholic Acid on Bile Acid Kinetics and Biliary Lipid Secretion in Humans

Transcription

1 GASTROENTEROLOGY 1983;85: Cmparative Effects f Ursdexychlic Acid and Chendexychlic Acid n Bile Acid Kinetics and Biliary Lipid Secretin in Humans Evidence fr Different Mdes f Actin n Bile Acid Synthesis KLAS NILSELL, BO ANGELIN, BARBRO LEIJD, and KURT EINARSSON Departments f Medicine and Surgery, Karlinska Institutet at Huddinge University Hspital, Stckhlm, Sweden The effects f ursdexychlic acid n biliary lipid secretin and bile acid kinetics were determined in 12 men, Fr cmparisn, eight f the subjects were als treated with chendexychlic acid using a crssver study design. The daily dse f each bile acid was 15 mg/kg bdy wt; each treatment perid lasted fr 5-6 wk. Kinetics f chlic acid and chendexychlic acid, hepatic secretin rates f biliary lipids, and lipid cmpsitin f cncentrated fasting dudenal bile were determined befre and at the end f each treatment perid. The synthesis rates f chlic acid and chendexychlic acid were increased by ~80% and 40%, respectively, during treatment with ursdexychlic acid. The fractinal catablic rates f the tw bile acids were increased by ~50%, whereas the pl sizes remained unchanged. Under similar cnditins, administratin f chendexychlic acid reduced the pl size as well as the synthesis rate f chlic acid by ~70%. Ursdexychlic acid reduced the hepatic secretin f chlesterl t a higher extent (~50%) than did chendexychlic acid (~30%). The secretin rates Received February 28, Accepted June 8, Address requests fr reprints t: Klas Nilsell, M.D., Department f Surgery, Huddinge University Hspital, S Huddinge, Sweden. This study was supprted by grants frm the Swedish Medical Research Cuncil (03X-04793), the Karlinska Institutet, the L and Hans Osterman Fundatin, and the Swedish Sciety f Medical Sciences. Dr. Angelin was supprted by a fellwship grant frm the Ernst Klenk Fundatin. The authrs thank Ms. Ann-Christine Anderssn and Ms. Lisbeth Benthin fr their technical assistance, and Ms. Lena Ericssn fr help in preparing the manuscript. 1!l83 by the American Gastrenterlgical Assciatin ~ /83/$3. f bile acids and phsphlipids remained essentially unchanged during the tw treatment perids. Fasting dudenal (gallbladder) bile was unsaturated with chlesterl during bth regimens. It is cncluded that the tw bile acids exert different effects n bile acid metablism. The enhanced cnversin f chlesterl t bile acids bserved during ursdexychlic acid treatment may at least partly explain why ursdexychlic acid can reduce the biliary utput f chlesterl withut suppressing hepatic chlesterl synthesis. Oral administratin f chendexychlic acid (CDCA) as well as ursdexychlic acid (UDCA) t patients with gallstnes reduces chlesterl saturatin f bile and may induce disslutin f chlesterl gallstnes (1-5). Bth are naturally ccurring bile acids and differ in structure nly in the rientatin f the hydrxyl grup at the C-7 psitin. Side effects, such as diarrhea and hypertransaminasemia, which are ften bserved during CDCA therapy, are nt seen during treatment with UDCA. Furthermre, it has been bserved that UDCA decreases chlesterl saturatin f bile at a lwer dsage than des CDCA (6,7). The decreased chlesterl saturatin bserved during CDCA feeding is due t a reductin f biliary chlesterl secretin; the secretin rates f bile acids and phsphlipids are essentially unchanged (8,9). The bile acid pl becmes cmpsed predminantly (~80%) f CDCA because the frmatin f chlic acid (CA) is suppressed (10,11). During UDCA feeding, n the ther hand, the relative enrichment f this bile acid is less prnunced, ~50% (5-7). Hwever, in spite f the lwer enrichment f UDCA in

2 December 1983 EFFECTS OF UDCA ON BILE ACID KINETICS 1249 Table 1. Basal Data f the Subjects Bdy weight Serum Serum Patient Age Relative" chlesterl b trigl ycerides c number (yr) kg % (mmlll) (mmlll) Clinical histry 1 L.A S.M S.E.S Chlecystectmy; crnary heart disease 4 J.V p.a K.E B.J Crnary heart disease 8 B.K H.N K.P N.S S.S Crnary heart disease a Calculated as {bdy weight (kg)/[height (cm) - 1]) x 1%. b T cnvert t mg/dl, multiply by C T cnvert t mg/dl, multiply by bile during treatment with this bile acid, the hepatic secretin f chlesterl seems t be reduced mre by UDCA than by CDCA (12). The reasns fr this difference are nt knwn, and the effects f UDCA n hepatic bisynthesis f bile acids have nt been fully characterized (fr an extensive recent review, see reference 5). The apparent advantages f UDCA will prbably lead t increased use f this bile acid in the treatment f chlesterl gallstnes in the future. It is, therefre, f great imprtance t define the effects f UDCA n biliary lipid metablism. The present study was undertaken t cmpare the influence f UDCA and CDCA n biliary lipid cmpsitin, bile acid kinetics, and biliary lipid secretin rates in humans. Materia:ls and Methds Subjects The present study cmprised 12 nnbese male subjects, seven f whm had hyperlipidemia. Nne shwed evidence f intestinal, hepatic, thyrid, r renal disease, r addictin t alchl r narctics. Patient N.3 had undergne a chlecystectmy, and the thers were free frm gallstne disease as judged frm ral chlecystgraphy. The clinical data f the patients are listed in Table 1. Infrmed cnsent was btained frm each subject. Experimental Prcedure The patients were studied befre and during treatment with UDCA. Eight f the patients were als treated with CDCA. The daily dse f bile acid was 15 mg/kg bdy wt, and each treatment perid lasted 5-6 wk. The medicatin was well tlerated. Mst f the subjects treated with CDCA nted sfter stls, and ne develped ccasinal diarrhea. Bdy weights remained unchanged. Mst f the patients were hspitalized during the study perid, and the thers were fllwed clsely n an utpatient basis. During each study perid, the pl size, synthesis, and fractinal turnver rate f CA and CDCA were determined. During the CDCA perid, nly the kinetics f CA were studied. Furthermre, the hepatic secretin rates f biliary lipids were measured. Als, the cmpsitin f bile acids and biliary lipids and the chlesterl saturatin f cncentrated fasting dudenal bile (btained after chlecystkinin administratin during the kinetic studies) were determined during each perid. Materials Ursdexychlic acid was kindly supplied by Tky Tanabe C., Tky, Japan, and was shwn t be >98% pure by gas-liquid chrmatgraphy. The cntaminant was almst exclusively CDCA. Ursdexychlic acid was administered in 125-mg (0.32 mml) capsules twice daily. Chendexychlic acid (Chendal) was btained frm Drac, Sweden, and administered in 125-mg (0.32 mml) capsules twice daily. This preparatin was >99% pure. [24-14 CJChlic acid (138,uCi/mg) and [24-14 C1CDCA (138,uCi/mg) were purchased frm New England Nuclear Crp., Bstn, Mass. 3a-Hydrxysterid dehydrgenase (Stergnst) and chlesterl xidase (Nyc-test chlesterl) were purchased frm Nyegaard A/S, Osl, Nrway. Measurement f Bile Acid Kinetics and Biliary Bile Acid Cmpsitin The sdium salts f [ 14 C1CA (4,uCi) and [ 14 C1CDCA (4,uCi) disslved in water were administered rally as a mixture in the mrning befre breakfast. Fur samples f fasting dudenal bile were cllected after intravenus injectin f chlecystkinin frm each subject at intervals M 1-3 days. The dudenal bile samples were hydr6lyzed

3 1250 NILSELL ET AL. GASTROENTEROLOGY Vl. 85. N.6 with 1 M ptassium hydrxide in clsed steel tubes fr 12 h at 110 C. The decnjugated bile acids were extracted with ethyl ether after acidificatin, and their methyl esters were separated by thin-layer chrmatgraphy. One aliqut was then quantitated with gas-liquid chrmatgraphy after preparatin f the trimethylsilyl ether derivates. A 1 % Hi-Eff BP 8 clumn was used. Anther aliqut frm this extract was analyzed fr radiactivity by liquid scintillatin. On the basis f the specific radiactivity curve, the pl size, daily synthesis, and fractinal turnver rate fr CA and CDCA were calculated as described by Lindstedt (13). Fr determinatin f bile acid cmpsitin, an aliqut f the decnjugated bile acid extract was methylated, trimethylsilylated, and analyzed by gas-liquid chrmatgraphy using a 1% Hi-Eff BP 8 clumn. The respnse f the individual bile acids was checked repeatedly. Analysis f Biliary Lipids Fr determinatin f chlesterl and phsphlipids, a prtin f the bile samples btained was immediately extracted with 20 vl f chlrfrm-methanl, 2:1 (vllvl). Chlesterl was determined by an enzymatic methd (14) and phsphlipids by the methd f Ruser et al. (15). The ttal bile acid cncentratin in ne aliqut f the bile samples was determined using a 3a-hydrxysterid dehydrgenase assay (16). The cefficients f variatin f the methds fr analyzing chlesterl. phsphlipids. and bile acids were 4%. 3%. and 3%. respectively. Calculatins f Chlesterl Saturatin f Dudenal Bile Chlesterl slubility was calculated as a percentage f the predicted chlesterl slubility at the respective biliary lipid cmpsitin. as described by Carey (17). The ttal lipid cncentratin was assumed t be 10 g/dl in cncentrated fasting dudenal (gallbladder) bile and 3 g/dl in hepatic bile (ef. 18). In the UDCA-treated patients. the chlesterl saturatin f gallbladder bile was calculated bth with and withut the crrectin factr fr UDCA-rich bile. as prpsed by Carey (17). Hepatic Secretin Rates f Biliary Lipids An intestinal perfusin technique. riginally described by Grundy and Metzger (19) and mdified by Shaffer and Small (20), was used. The subjects were intubated with a triple-lumen plyvinyl tube. The infusin site was psitined flurscpically in the dudenum at the ampulla f Vater, the prximal cllecting rifice 2 cm and the distal cllecting rifice 12 cm distally. just beynd the ligament f Treitz. A mixture f 5% glucse and amin acids (Vamin. Vitrum). t which had been added essential amin acids (L-methinine. 40 mm. L-valine, 25.8 mm. and L-phenylalanine mm) and brmsulphalein (BSP) as an unabsrbable marker. was infused cnstantly at a rate f 5 mllmin. After an equilibratin perid f 3-4 h. hurly samples f 10 ml were drawn by cntinuus aspiratin frm the secnd prximal and the distal utlets. The sampling was discntinued after anther 6-7 h. The hurly secretin rate f chlesterl was determined frm measurement f the rati f chlesterl t marker at the distal utlet. The secretin rates f bile acids and phsphlipids were btained frm the ratis f bile acids and phsphlipids t chlesterl in the prximal samples. Kern et al. (21) have recently presented evidence that infusin f a liquid frmula cntaining fat stimulates gallbladder emptying and bile acid secretin mre effectively than a mixture f essential amin acids. The secretin rates in ur subjects. hwever. were higher than thse btained by these authrs as well as by Shaffer and Small (20). This is prbably because we used a higher infusin rate. Furthermre. ne f us (B.A.) has recently determined the biliary secretin f a parenterally administered antibitic using the same technique in healthy subjects with intact gallbladder (22). A very stable excretin rate f this exgenus cmpund was demnstrated. indicating that the gallbladder remained cntracted during the study perid. It seems reasnable. therefre. t assume that ur biliary lipid secretin rates represent maximum rates f secretin. Statistical Analysis Data are presented as means :!:: SEM. The statistical significance f differences was evaluated with Wilcxn's signed rank test fr paired bservatins (23). Results Plasma Lipid Levels The plasma cncentratin f chlesterl did nt change significantly during the treatment perid fr either the healthy vlunteers r the hyperlipidemic subjects. The mean values were 6.3 ± 0.5, 6.2 ± 0.4, and 6.8 ± 0.4 mmlil during the cntrl perid, UDCA-treatment perid. and CDCA-treatment perid. respectively. Als, the plasma cncentratins f triglycerides remained essentially unchanged in bth grups. Mean values were 3.0 ± 0.6, 3.1 ± 0.6, and 2.8 ± 0.7 mmlil during the cntrl perid, UDCA-treatment perid, and CDCA-treatment perid, respectively. Bile Acid Cmpsitin Ursdexychlic acid cnstituted 50.0 ± 3.5% f the biliary bile acids in the UDCA-treated subjects (Table 2). Chlic acid, CDCA, and dexychlic acid (DCA) were cncmitantly decreased. Treatment with CDCA resulted in an increase f this bile acid t 78.7 ± 3.6% and in a decrease f CA and DCA. A slight increase f lithchlic acid (LCA) was seen during bth UDCA and CDCA treatment.

4 December 1983 EFFECTS OF UDCA ON BILE ACID KINETICS 1251 Table 2. Bile Acid Cmpsitin Befre and During Treatment With Ursdexychlic Acid and Chendexychlic Acid Perid (number f patients) CA CDCA DCA UDCA LCA Basal (n = 12) 41.1 ± ± ± ± 0.6 Trace UDCA (n = 12) 19.8 ± 1.8 b 19.1 ± 1.5 b 10.0 ± 1.0b 50.0 ± 3.5 b 1.1 ± CDCA (n = 8) 12.9 ± 2.5 b 78.7 ± 3.6 b 3.4 ± LOb 4.4 ± ± 0.3 b All values are mean ± SEM. CA = chlic acid. CDCA = chendexychlic acid. PCA = dexychlic acid. UDCA = ursdexychlic acid. LCA = lithchlic acid. a Significantly different frm crrespnding value during basal perid, p < b Significantly different frm crrespnding value during basal perid, p < Biliary Lipid Cmpsitin Treatment with UDCA and CDCA gave a decrease in the relative cncentratin f chlesterl in cncentrated fasting dudenal (gallbladder) bile, frm 7.0 ± 0.8% t 3.0 ± 0.4% and 4.3 ± 0.6%, respectively (Table 3). The relative cncentratin f bile acids was slightly increased during UDCAfeeding (frm 73.3 ± 1.8 t 76.2 ± 2.0%, p<0.02) but remained unchanged during CDC A feeding. The phsphlipid fractin remained essentially unchanged during the treatment perids. Gallbladder bile tended t be mre saturated in the hypertriglyceridemic patients (mean value, 122%) than in the nrmlipidemic subjects (mean value, 78%) in the untreated state. Ursdexychlic acid as well as CDCA made gallbladder bile unsaturated in all subjects. In fact, bile became mre unsaturated during UDCA (45 ± 5%) than during CDCA treatment (60 ± 6%) if Carey's crrectin factr fr UDCA-rich bile was nt taken int accunt. With the crrectin factr, chlesterl saturatin was 64 ± 6%. In stimulated hepatic bile, the relative cncentratin f chlesterl averaged 4.9 ± 0.8% under basal cnditins and 2.9 ± 0.4% and 3.1 ± 0.6% during administratin f UDCA and CDCA, respectively (Table 4). Crrespnding values f chlesterl saturatin were 104 ± 13%, 67 ± 9%, and 62 ± 11%, respectively. Kinetics f Chlk Acid and Chendexychlic Acid Under basal cnditins, the pl size, synthesis, and fractinal catablic rate (FCR) f CA averaged 2.95 ± 0.62 mml, 1.06 ± 0.16 mmllday, and ± per day, respectively (Table 5). The pl size f CA was unchanged during treatment with UDCA, whereas the synthesis rate was increased, n the average, by ~80% in 10 f the 12 subjects. This was assciated with r due t a higher FCR. Administratin f CDCA was assciated with a 70% reductin f bth pl size and synthesis f CA, whereas the FCR was nt affected. The pl size, synthesis, and FCR f CDCA averaged 2.36 ± 0.38 mml, 0.74 ± 0.11 mmllday, and ± per day, respectively (Table 6). Urs- Table 3. Chlesterl Cncentratin and Saturatin f Gallbladder Bile Befre and During Treatment With Ursdexychlic Acid and Chendexychlic Acid Saturatin, %a Patient Chlesterl, mlar % Crrected number Basal UDCA CDCA Basal UDCA UDCA b CDCA 1 L.A S.M S.E.S J.V p.a K.E B.J B.K H.N K.P N.S S.S Mean ± SEM 7.0 ± ± 0.4" 4.3 ± 0.6 c. d 103 ± ± 5" 64 ± 6" 60 ± 6",d Results are expressed as individual values and mean ± SEM. See Table 2 fr key t abbreviatins. 0 Assuming a lipid cncentratin f 10 g/1 ml (17). b Crrected fr the percentage f UDCA in bile accrding t Carey (17). " Significantly different frm crrespnding value during basal perid, p < d Significantly different frm crrespnding value during UDCA-treatment perid, p < 0,05.

5 1252 NILSELL ET AL. GASTROENTEROLOGY Vl. 85, N.6 Table 4. Chlesterl Cncentratin and Saturatin f Stimulated Hepatic Bile Befre and During Treatment With Ursdexychlic Acid and Chendexychlic Acid Chlesterl, mlar % Saturatin, %a Patient number Basal UDCA CDCA Basal UDCA CDCA 1 L.A S.M S.E.S J.V p.a K.E B.J B.K H.N K.P S.S Mean ± SEM 4.9 ± ± 0.4c 3.1 ± ± ± 9 c 62 ± 11 b See Table 2 fr key t abbreviatins. Q Assuming a lipid cncentratin f 3 g/1 ml (17). b Significantly different frm crrespnding value during basal perid, p < C Significantly different frm crrespnding value during basal perid, p < dexychlic acid treatment did nt change the pl size f CDCA, but the synthesis was increased in all subjects but ne, n the average by ~40%. The FCR was increased by ~50%. Biliary Lipid Secretin Rates Table 7 summarizes the results. The secretin rate f chlesterl befre treatment tended t be higher in the hypertriglyceridemic patients (mean value 104 flmllh) than in the nrmlipidemic subjects (mean value 68 flmllh). In all subjects, UDCA decreased the chlesterl secretin, n the average by ~50%. Chendexychlic acid als reduced the chlesterl secretin, but t a lesser extent (~30%). The secretin f bile acids was nt cnsistently affected during the bile acid feeding perids. Neither was the phsphlipid secretin changed by CDCA treatment. There was a tendency t a lwer secretin rate f phsphlipids during the UDCA perid, since 8 f the 11 subjects had lwer values, but the difference did nt reach statistical significance. Discussin A majr new finding in the present study was that UDCA treatment did nt suppress the frmatin f bile acids. Instead, the synthesis rates f the tw primary bile acids, CA and CDCA, were increased in mst f the subjects studied. Under the same cnditins, CDCA inhibited the frmatin f CA, which is in accrdance with previus reprts (10,11). The pl sizes f CA and CDCA were unchanged during UDCA treatment, indicating that the ttal bile acid pl was increased. The augmented synthesis rates f CA and CDCA were explained by higher FCR. It cannt be stated fr certain that the endgenus synthesis f CDCA was increased, since this bile acid may have been frmed, t sme extent, frm UDCA (24). The endgenus frmatin f CA, hwever, must have been increased. Indirect evidence that UDCA des nt suppress the synthesis f CA was recently btained by Thistle et al. (7) wh studied the pattern f fecal bile acids during UDCA and CDCA treatment. Several pssible explanatins fr this finding may be cnsidered. First, UDCA may be a weaker inhibitr f bile acid bisynthesis than CDCA. Bile acid frmatin is assumed t be regulated by the prtal inflw f bile acids t the liver, presumably via mdulatin f the activity f the rate-determining enzyme, 7 a-hydrxylase (25). Interruptin f the enterhepatic circulatin f bile acids leads t a cmpensatry increase in bile acid synthesis. As the ttal bile acid secretin rate remained unchanged bth during UDCA and CDCA therapy, the prtal inflw f ttal bile acids shuld have been the same during the tw treatment perids. Since CDCA was the predminant bile acid during CDCA therapy and UDCA was the majr bile acid during administratin f this bile acid, it seems reasnable t assume that UDCA is a weaker suppressr f bile acid synthesis (and the 7 a-hydrxylase) in humans. Secnd, UDCA may interfere with the intestinal absrptin f CA. The increased FCR wuld be cmpatible with such a mechanism. Hw UDCA wuld interfere with CA absrptin can nly be speculated upn. During UDCA treatment, bile acids becme cnjugated mainly with glycine (26). At physilgic ph values, the glycine cnjugate f UDCA is the mst insluble f the cmmn bile acids, and it may precipitate in the intestine at high

6 December 1983 EFFECTS OF UDCA ON BILE ACID IGNETICS < U Q U ON<::tLf')CO <::t::t-<::ton MCO<::tNt CONO::rr--.. ~MCONCO... 0 MCOLf)t--.N Lf')MM~O') ~~6 0 ~ ~ I I I ';< '" I I I I I I ",,,,"'''''''''''''''''''''''''' 0 "- 0) +1 '" ~ ~ +1 ".q 'c a ;:l '" "0 +1 ~ ;; "- :a " " P, <Jl u :; ~ ~ : ~ ~ ~ ~ g ~ ~ ~ +1 e 66~66~6066 ~ ~ ~ c... ':S 6 "0 ~ ~MCONNO,)NMt-..-=:t'M 0 'E Lf') M CO t--. ::r 0 0') CO <::t MO')O') +1 CO ~~MOONNN~~N6 ~ ~ CO "2 CI3 N ~ "u; (3 - E ~~ ' (3 M Lf) ~ M Lf) M M CO CO ::r CO ::r -6 CC!~~CC!~~~~~c:c:~ 06 Cl")CI")N~~NN::r~NM::r 0':- 0':-....n a ;:l " "'",.;<""'"''''0) 0 N Lf) L!") N <::t '!"""'4 CO t--. CO CO 0 CO +1 ~O~~O~~ciOON6 CO M<::tCO'!"""'4NCOMONt--.<::tO ~U-:~~~~r;~~CC!Lf')r-4 CV")r-4<::tNNMNr-Ir-4r-4NO'). cti. C ~~~>~~~~~.;cti0 1i -lrjjrjj,""""...::'::~~::c::'::zrjj 0... '" ~ cncentratins (27). This culd result in precipitatin f ther bile acids presen.t. Anther pssibility is that UDCA cmpetes with CA at the acltive site f bile acid absrptin in the distal part f l'he ileum. Ursdexychlic acid and its c njugates, when inized, are mre hydrphilic than CA (28), which may affect binding t the active sites. S~uch a mechanism, hwever, is unlikely t explain the increased FCR f CDCA seen during UDCA treatment'. Bile acid inductin f bacterial enzymes culd. "3.1 s mdify the prprtins f bile acids., althugh this wuld seem t be less likely fr UDCA (29). It will be f interest t determine whether similar effects r. 1 CA synthesis and FCR ccur when lwer dsages f UDCA are used, and if the effect 'can be prevent ed by dietary supplementatin with taurine (30). ',(he different effect f UDCA and CD'CA n CA synthe. ~sis is prbably the main reasn why the percentage, <; f CA and DCA in bile are neve:r reduced t the Sl1me extent during treatment with UDCA as with CDC ~A (5-7). Anther imprtant result in the present wrk was the effects f UDCA and CDCA n the hepatic utputs f biliary lipids. In accrdance Witl'l previus reprts (8,9), we fund that CDCA treatme. mt was assciated with a delcreased secretin f chle. ~'terl; the secretin rates f bile acids and phsphll ipids were essentially un changed. Ursdexychlic acid decreased the secpetin f chlesterl even II.lOre than CDCA, but did nt significantly affect the sec retin rates f bile 81cids and phsphlipids. Durillg the curse f thif; investigatin, Leiss et al. (1::") reprted n a simi lar study in gallstne patients. In agreement with,ur data, they fund that UDCA reduces the biliary secretin f chlesterl mre than CDCA; hwever, they nted a slight increase in bile acid secreti n during UDCA treatment. Althugh it is ps sible that bile acid secretin may increase during administratin f UDCA in sme patients, the de saturating effect f UDCA in gallstne patients, as well as in gallstne-free subjects, is thus mainly attributalble t its actin n chlesterl secretin. The mechani:sm whereby UDCA and CDCA decrease chlesterl secretin may nt be the same fr the tw bile acids. The reduced utput f chlesterl during CDC A treatment has been attributed t a direct r indirect suppressin f the rate-limiting enzyme in hepatic chlesterl synthesis, 3-hydrxy- 3-methylglutaryl cenzyme A (HMG CAl reductase (31). There is sme cntrversy in the literature with regard t the effect f UDCA n HMG CA reductase activity (see mference 5). Hwever, under similar experimental cnditins as thse described fr CDCA, we did nt bserve a significant influence n hepatic HMG ea reductase activity by UDCA treatment in spite f an equal degree f unsaturatin f

7 1254 NILSELL ET AL. GASTROENTEROLOGY V!' 85, N. 6 Table 6. Kinetics f Chendexychlic Acid Befre and During Treatment With Ursdexychlic Acid Basal UDCA treatment Fractinal Fractinal P'l ~;ize Synthesis catablic rate Pl size Synthesis catablic rate Patient number (mml) (mmllday) per day (mml) (mmllday) per day 1 L.A S.M S.E.S J.V p.a K.E B.J B.K H.N K.P N.S S.S Mean ± SEM 2.36 ± ± ± ± ± 0.16" ± b Results are ex pressed as individual data and mean ± SEM. See Table 2 fr key t explanatins. a Significantly different frm crrespndin,u; value during basal pe.rid, p < b Significantly different frm crrespnding value during basal perid, p < fasting hepatic bile (18). Ursdexychlic acid, therefr;1 e, suppresses the biliary utput f chlesterl by r nechanisms ther than by affecting hepatic chles'terl synthesis. One pssible mechanism may be a l'f ~duced inflw f chlestewl frm the intestine, i.e., 11 diminished absrptin f dietary chlesterl. Sup' prt fr this view has beem gained frm sme stu'dies, but nt frm thers (see.reference 5). Anther. factr f imprtance culd be the lw chlesterl ~.rjlubilizing capacity f UDCA CCtmpared with ther r ~mmn bile acids (32). Thus, experiments utilizing acute administratin f bile acids t patients have shwn that UDCA reduces the rate f chlesterl secretin cmpared with that induced by the patient's endgenus bile acids (33,34). These results culd suggest that UDCA exerts a direct effect n chlesterl secretin by being a less efficient detergent (35). Prlnged treatment with UDCA, hwever, des nt lead t an enhanced hepatic cncentratin f chlesterl (18). Furthermre, it culd be speculated that UDCA affects the hepatic uptake and metablism f lipprteins (36). Chendexychlic acid treatment is assciated with a reductin f plasma very-lw-density lipprteins and an increase f lw-density lipprteins (37-39). Such changes, hwever, have nt been bserved during UDCA treatment (18,40). It is f interest t cnsider that the increase in the Table 7. Hepatic Lipid Secretin Rates Befre and During Treatment With Ursdexychlic Acid and Chendexychlic Acid Chlesterl secretin (J.Llpllh) Bile acid secretin (J.Lmllh) Phsphlipid secretin (J.Lmllh) Pretreat- Pretreat- Pretreat- Patient number ment UDCA COCA ment UDCA CDC A ment UDCA CDCA 1 L.A S.M S.E.S J.V p.a K.E B.J B.K H.N K.P S Mean ± SEM 87 ± ± 5 b 60 :±: 5 c 1677 ± ± ± ± ± ± 59 Results are expressed as individual data and mean ± SEM. See Table 2 fr key t abbreviatins. a Significantly different frm crrespnding value during cntrl perid, p <: b Significantly different frm crrespnding value during cntrl perid, p < C Significantly different frm crrespnding value during UDCA-treatment perid, p < 0.05.

8 December 1983 EFFECTS OF UDCA ON BILE ACID KINETICS 1255 cnversin f chlesterl t bile acids bserved in the present study (~1 mmllday) is sufficient t accunt fr all f the reductin in hepatic secretin f chlesterl (~1 mmllday). Thus, prvided that the hepatic chlesterl synthesis is unaffected, that the absrptin f chlesterl frm the intestine is reduced r unchanged, and that the inflw f lipprtein chlesterl t the liver is als unchanged, the enhanced bile acid prductin induced by UDCA treatment wuld result in less hepatic chlesterl available fr direct excretin int the bile. This mechanism may prve t be a factr f majr imprtance in explaining the changes in chlesterl saturatin f bile induced by UDCA treatment. References 1. Thistle JL, Hfmann AF, Ott BJ, et al. Chentherapy fr gallstne disslutin. r. Efficacy and safety. JAMA 1978;239: Hfmann AF, Thistle JL, Klein PD, et al. Chentherapy fr gallstne disslutin. II. Induced changes in bile cmpsitin and gallstne respnse. JAMA 1978;239: Tky Cperative Gallstne Study Grup. Efficacy and indicatins f ursdexychlic acid treatment fr disslving gallstnes. A multicenter duble-blind trial. Gastrenterlgy 1980;78: Schenfield LJ, Lachin JM. Chendil (chendexychlic acid) fr disslutin f gallstnes: the Natinal Cperative Gallstne Study. A cntrlled trial f efficacy and safety. Ann Intern Med 1981;95: Bachrach WH, Hfmann AF. Ursdexychlic acid in the treatment f chlesterl chlelithiasis. Dig Dis Sci 1982;27:737-61, Stiehl A, Czygan P, Kmmerell B, et al. Ursdexychlic acid versus chendexychlic acid: cmparisn f their effects n bile acid and bile lipid cmpsitin in patients with chlesterl gallstnes. Gastrenterlgy 1978;75: Thistle JL, LaRuss NF, Hfmann AF, et al. Differing effects f ursdexychlic r chendexychlic acid n biliary chlesterl saturatin and bile acid metablism in man. Dig Dis Sci 1982:27: Adler RD, Bennin LJ, Duane WC, et al. Effects f lw dse chendexychlic acid feeding n biliary lipid metablism. Gastrenterlgy 1975;68: LaRuss NF, Hffman NE, Hfmann AF, et al. Effect f primary bile acid ingestin n bile acid metablism and biliary lipid secretin in gallstne patients. Gastrenterlgy 1975;68: Danzinger RG, Hfmann AF, Thistle JL, et al. Effect f ral chendexychlic acid n bile acid kinetics and biliary lipid cmpsitin in wmen with chlelithiasis. J Clin Invest 1973;52: Kallner M. The effect f chendexychlic acid feeding n bile acid kinetics and fecal neutral sterid excretin in patients with hyperlipprteinemia types II and IV. J Lab Clin Med 1975;86: Leiss 0, Bsch T, vn Bergmann K. Effects f bile acid feeding n lipprtein cncentratin, change in chlesterl synthesis and biliary lipid secretin in patients with radilucent gallstnes. In: Paumgartner G, Stiehl A, Gerk W, eds. Bile acids and lipids, Lndn: MTP Press, 1981: Lindstedt S. The turnver f chlic acid in man. Acta Physil Scand 1957;40: Rda A, Festa D, Sarna C, et al. Enzymatic determinatin f chlesterl in bile. Clin Chim Acta 1975;64: Ruser G, Sidney F, Akira Y. Tw dimensinal thin-layer chrmatgraphy separatin f plar lipids and determinatins f phsphrus analysis f spts. Lipids 1970;5: Fausa 0, Skalhegg BA. Quantitative determinatin f bile acids and their cnjugates using thin-layer chrmatgraphy and purified 3 a-hydrxysterid dehydrgenase. Scand J Gastrenterl 1974;9: Carey Me. Critical tables fr calculating the chlesterl saturatin f native bile. J Lipid Res 1978;19: Angelin B, Ewerth S, Einarssn K. Ursdexychlic acid treatment in chlesterl gallstne disease: effects n hepatic 3-hydrxy-3-methylglutaryl cenzyme A reductase, biliary lipid cmpsitin, and plasma lipid levels. J Lipid Res 1983;24: Grundy SM, Metzger AL. A physilgical methd fr estimatin f hepatic secretin f biliary lipids in man. Gastrenterlgy 1972;62: Shaffer EA, Small DM. Biliary lipid secretin in chlesterl gallstne disease: the effect f chlecystectmy and besity. J Clin Invest 1977;59: Kern F Jr, Eversn GT, DeMark B, et al. Biliary lipids, bile acids, and gallbladder functin in the human female: effects f pregnancy and the vulatry cycle. J Clin Invest 1981;68: Arvidssn A, Alvan G, Angelin B, et al. Ceftriaxne: renal and biliary excretin and effect n the cln micrflra. J Antimicrb Chemther 1982;10: Snedecr GW, Cchran WG. Statistical methds. 6th ed. Ames, Iwa: Iwa State University Press, Fedrwski T, Sal en G, Clallit A, et al. Metablism f ursdexychlic acid in man. Gastrenterlgy 1977; 73: Myant NB, Mitrpuls KA. Chlesterl 7 a-hydrxylase. J Lipid Res 1977;18: Stiehl A, Raedsch R, Czygan P, et al. Effects f biliary bile acid cmpsitin n biliary chlesterl saturatin in gallstne patients treated with chendexychlic acid and/r ursdexychlic acid. Gastrenterlgy 1980;79: Igimi H, Carey Me. ph-slubility relatins f chendexychlic and ursa dexychlic acids: physical-chemical basis fr dissimilar slutin and membrane phenmena. J Lipid Res 1980;21: Armstrng MJ, Carey MC. The hydrphbic-hydrphilic balance f bile salts. Inverse crrelatin between reverse-phase high perfrmance liquid chrmatgraphy mbilities and micellar chlesterl-slubilizing capacities. J Lipid Res 1982;23: MacDnald la, Rach PD. Bile inductin f 7 alpha- and 7 beta-hydrxysterid dehydrgenase in Clstridium absnum. Bichim Biphys Acta 1981;665: Batta AK, Salen G, Shefer S, et al. The effect f taurursdexychlic acid and taurine supplementatin n biliary bile acid cmpsitin. Hepatlgy 1982;2: Ahlberg J, Angelin B, Einarssn K. Hepatic 3-hydrxy-3- methylglutaryl cenzyme A reductase activity and biliary lipid cmpsitin in man: relatin t chlesterl gallstne disease and effects f chlic acid and chendexychlic acid treatment. J Lipid Res 1981;22: Carey MC, K G. The imprtance f ttal lipid cncentratin in determining chlesterl slubility in bile and the develpment f critical tables fr calculating percent chlesterl saturatin with a crrectin factr fr ursdexychlate-rich bile. In: Paumgartner G, Stiehl A, Gerk W, eds. Bilgical effects f bile acids. Lndn: MTP Press, 1979: Schersten T, Lindblad 1. Biliary chlesterl utput during

9 1256 NILS ELL ET AL. GASTROENTEROLOGY Vl. 85. N.6 ursdexychlic acid secretin in man. In: Paumgartner G. Stiehl A. Gerk W. eds. Bilgical effects f bile acids. Lndn: MTP Press. 1979: Sarna C. LaRuss NF. Lpez del Pin V. et al. Effects f acute bile acid administratin n biliary lipid secretin in healthy vlunteers. Gastrenterlgy 1982:82: Carey MC. Mnet JC. Phillips MC. et al. Thermdynamic and mlecular basis fr dissimilar chlesterl-slubilizing capacities by micellar slutins f bile salts: cases f sdium chendexychlate and sdium ursdexychlate and their glycine and taurine cnjugates. Bichemistry 1981;20: Angelin B. Ravila CA. Innerarity TL. et al. Regulatin f hepatic lipprtein receptrs in the dg. Rapid regulatin f aplipprtein B.E receptrs. but nt f aplipprtein E receptrs by intestinal lipprteins and bile acids. J Clin Invest 1983;71: Angelin B. Einarssn K. Leijd B. Clfibrate treatment and bile chlesterl saturatin: shrt-term and lng-term effects and influence f cmbinatin with chendexychlic acid. Eur J Clin Invest 1981;11: Albers JJ. Grundy SM. Cleary PA. et al. Natinal Cperative Gallstne Study: the effect f chendexychlic acid n lipprteins and aplipprteins. Gastrenterlgy 1982;82: Leijd B. Angelin B. Effects f chendexychlic acid and chlic acid feeding n plasma lipprteins and chlesterl absrptin in hyperlipprteinemia. In: Paumgartner G. Stiehl A. Gerk W. eds. Bile acids and chlesterl in health and disease. Lndn: MTP Press. 1983: Angelin B. Einarssn K. Leijd B. Bile acids and triglyceride metablism in man. In: Paumgartner G. Stiehl A. Gerk W. eds. Bile acids and lipids. Lndn: MTP Press. i981: