- Email: [email protected]
Pharmacokinetic of lansoprazole in cirrhotics with different degree of liver function derangement
April 1 9 9 5
• PHARMACOKINETIC OF LANSOPRAZOLE IN CIRRHOTICS WITH DIFFERENT DEGREE OF LIVER FUNCTION DERANGEMENT S. SIRINGO, L. BOLONDI, L. GRAMANTIER1, G. GERMANO, M. MIGLIOLI~ L. BARBARA. ]STITUTODI CLINICA MEDICA [ . UNIVERSITADI BOLOGNA- ITALY Lansoprazole is a proton pump inhibitor that inhibits gastric acid secretion and whom t½ in healthy volunteer is 1.4 hr. (Eur. J. Pharmaeol. 1993;45:367). Lansoprazole is metabolized in the liver and its pharmacokinetic might be altered in cirrhotic patients. This, in turn may require dosages adjustment according to the severity of cirrhosis. Aim of the present study was to assess the 48 hr. pharmacokinetic of LANSOPRAZOLE in relation to the degree of liver function impairment in patients with liver cirrhosis. We studied 25 cirrhotic patients: 84% male, mean age 57.2 years. The severity of liver function impairment was assessed according to the Child-Campbell's criteria: 14 patients were in A class and 11 in B/C class. Lansoprazole (Takeda ®) was given as a single 30 mg oral dosage. Blood sample were taken before drug administration (time 0) and 1, 2, 3, 6, 9, 12, 24, 48 hr. after Lansoprazole. Urine were collected at time 0 and at 12 hr. intervals after Lansoprazolel Lansoprazole and metabolites AGI908, AG1813, AG1777 were measured in plasma and Lansoprazole and metabolites AG1908, AGt909, AG 1907, were measured in urine, respectively, by HPLC with UV detection. The table reports the Lansoprazole pharmacokinetic parameters. LANSOPRAZOLE Child A (n=14) Child B/C (n=l 1) P Cmax (n~ ml-!) (5: SD) 1058.9(5: 391.9) 965.0 (+ 305.9) N.S. tmax (hrs)) (5: SD) 2.8(5:2.5) 2.5(5:1.4) N.S. AUCn~ (+SD) 11073.1 (5:2991.1) 10976.1(5:3537.9) N.S. ttA (hrs) (ng ml-l) (_+SD) 7.5(5:2.1) [ 7.7(+1.6) N.S. After a single oral dosage of Lansoprazole 30 mg there were not significant differences in the pharmacokinetie parameters of Lansoprazole and its metabolites in plasma and urine between patients in Child-Campbell's A class with respect those in B/C class. CONCLUSIONS. 1) Although in cirrhotics the Lansoprazole t½ is about seven fold longer when compared with healthy volunteers (Eur. J. Pharmaeol. 1993;45:367), the degree of liver function impairment does not substaraially alter the Lansoprazole pharmacokinetic parameters in cirrhoties with different severity of liver disease. 2) There is not the need for Lansoprazole dosage adjustment in patients with liver cirrhosis and different degree of liver function derangement.
• ETHANOL-INDUCED CHANGES IN GASTRIC MUCUS GL¥COPROTEIN GLYCOSYLATION IN GOLGI. A. Slomianv, S. Sano and B.L. Slomiany. Res. Ctr., UMDNJ, Newark, NJ 07103. Ethanol-induced damage of gastric mucosa is the consequence of its action at various levels of cellular functions, expressed in transcription, translation, transport, and intracellular modification. The aim of this study was to d e t e r m i n e w h e t h e r p r o d u c t i o n of m o d i f i e d mucus glycoprotein is linked to changes in apomucin or is f u r t h e r compounded by ethanol affecting posttranslational glycosylation. The in vitro systems of purified Golgi preparation from gastric mucosa and glycosylation buffer containing UDPGlc, UDP-Gal, UDP-GIcNAc, ATP-activated cytosol, and GTP or G T P F S w e r e a s s e m b l e d with 0 - 1 2 0 m M ethanol. The glycosylation was conducted for 15, 30 and 60 min, and quantitated by ELISA assay of digoxigenin reactive glycoproteins. The standardization of the assay was performed with fetuin and c r e a t i n e kinase, as p o s i t i v e and negative substrates, respective!y. In control samples, when vesicular transport was blocked with G T P ~ S , the g l y c o s y l a t i o n i n c r e a s e d in a time dependent manner, and after lh, increased by 6875%. In samples containing ethanol, the glycosylation was inhibited by 66% at 30 min with no further change in glycosylation in the next 30 min of incubation. The studies provide direct evidence that ethanol induces synthesis of mucin with modified carbohydrate substitution. The results also suggest that ethanol causes changes in glycosylation of other proteins which may have p r o f o u n d c o n s e q u e n c e s in c a r b o h y d r a t e s p e c i f i c immunological and inflammatory responses in chronic alcoholism. Supported by NIH, NIAAA grant #AA05858-13.
Esophageal, Gastric, and Duodenal Disorders
A221
• A COMPARISON OF CULTURE, HISTOLOGY, AND 13CUREA BREATH TESTS FOR DETECTION OF 14. PYLORI. N. Slepman, S. Cox, C. Olson. Abbott Laboratories, Abbott Park, IL. Three diagnostic techniques for detecting H. pyloriwere employed in four large, well-controlled, treatment studies. Cultures (Cx), histology x), and 13C-urea breath (UBT) tests were used to assess • pylori (Hp) status in multicanter US and European studies conducted in 13 countries in patients with duodenal ulcers and Hp infection. The pretreatment and 4-6 week follow-up results are displayed below:
~
4-6 Week Folfow.-uD Histology
Histology UBT negative positive total
neg 47 6 53
pos 67 708 775
total 114 714 828
neg 237 8 245
pos 41 339 380
total 278 347 625
Culture negative positive total
53 2 55
133 657 790
186 659 845
239 6 245
70 319 389
309 325 634
The sensitivities for UBT and Cx using Hx as the gold standard were 91% and 83% at pretreatment and 89% and 82% at 4-6 weeks respectively. The US and European results were similar when comparing Cx versus Hx; however, the UBT was considerably more sensitive in the European studies than in the US (98% compared to 86% in the US pretreatment). The results from these studies suggest Hx was the most sensitive test for detecting H. pylori. Cx is useful for verifying positive results but is limited because of the number of false-negatives due to the asymmetric distribution of H. pyloriin the mucosa and the difficulty in transporting and culturing the organism. The UBT proved useful in the European studies but a number of false-negatives in the US studies indicates the need for standardization.
ENHANCEMENT IN GASTRIC MUCOSAL LAMININ RECEPTOR EXPRESSION WITH ULCER HEALING BY SUCRALFATE. B.L. Slomianv. J. Piotrowski, S. Sano and A. Slomiany. Res. Ctr., UMDNJ, Newark, NJ 07103. The i n t e g r i t y of the e p i t h e l i a l p e r i m e t e r of g a s t r i c m u c o s a l d e f e n s e is m a i n t a i n e d t h r o u g h specific interaction of the e p i t h e l i a l cell surface integrin receptors with adhesive proteins of the extracellular matrix. This interaction is considered of s i g n i f i c a n c e to a v a r i e t y of processes associated with cellular proliferation and tissue repair involving cell migration to the site of damage. In this study, we assessed the effect of a n t i u l c e r agent, sucralfate, on the e x p r e s s i o n of m u c o s a l laminin r e c e p t o r d u r i n g chronic ulcer healing. Groups of rats with acetic acid-induced chronic gastric ulcers were treated twice daily for 20 consecutive days either with sucralfate at 100mg/kg or placebo, and then at d i f f e r e n t stages used for the q u a n t i t a t i o n of g a s t r i c m u c o s a l l a m i n i n receptor. The assays revealed that the ulcer healing was accompanied by an increase in m u c o s a l e x p r e s s i o n of l a m i n i n receptor. A 1.9-fold increase in the receptor e x p r e s s i o n o c c u r r e d by 3rd day f o l l o w i n g the development of ulcer and reached a maximum of 8.6fold increase by the 14th day when the ulcer was essentially healed. Accelerated ulcer healing (8 days) with sucralfate treatment was accompanied by a s i g n i f i c a n t e v a l u a t i o n in laminin r e c e p t o r expression. In c o m p a r i s o n to the controls, s u c r a l f a t e evoked a 2 . 8 - f o l d i n c r e a s e in the laminin receptor expression by the 3rd day of treatment, reached a maximum of 3.1-fold the 7th day of treatment, and remained elevated even after 20 days of treatment. The findings attest to the importance of laminin receptor expression in the sustenance of proliferative activities of gastric mucosa essential for ulcer healing, and show that sucralfate possesses the ability to initiate and promote these events.
• PHARMACOKINETIC OF LANSOPRAZOLE IN CIRRHOTICS WITH DIFFERENT DEGREE OF LIVER FUNCTION DERANGEMENT S. SIRINGO, L. BOLONDI, L. GRAMANTIER1, G. GERMANO, M. MIGLIOLI~ L. BARBARA. ]STITUTODI CLINICA MEDICA [ . UNIVERSITADI BOLOGNA- ITALY Lansoprazole is a proton pump inhibitor that inhibits gastric acid secretion and whom t½ in healthy volunteer is 1.4 hr. (Eur. J. Pharmaeol. 1993;45:367). Lansoprazole is metabolized in the liver and its pharmacokinetic might be altered in cirrhotic patients. This, in turn may require dosages adjustment according to the severity of cirrhosis. Aim of the present study was to assess the 48 hr. pharmacokinetic of LANSOPRAZOLE in relation to the degree of liver function impairment in patients with liver cirrhosis. We studied 25 cirrhotic patients: 84% male, mean age 57.2 years. The severity of liver function impairment was assessed according to the Child-Campbell's criteria: 14 patients were in A class and 11 in B/C class. Lansoprazole (Takeda ®) was given as a single 30 mg oral dosage. Blood sample were taken before drug administration (time 0) and 1, 2, 3, 6, 9, 12, 24, 48 hr. after Lansoprazole. Urine were collected at time 0 and at 12 hr. intervals after Lansoprazolel Lansoprazole and metabolites AGI908, AG1813, AG1777 were measured in plasma and Lansoprazole and metabolites AG1908, AGt909, AG 1907, were measured in urine, respectively, by HPLC with UV detection. The table reports the Lansoprazole pharmacokinetic parameters. LANSOPRAZOLE Child A (n=14) Child B/C (n=l 1) P Cmax (n~ ml-!) (5: SD) 1058.9(5: 391.9) 965.0 (+ 305.9) N.S. tmax (hrs)) (5: SD) 2.8(5:2.5) 2.5(5:1.4) N.S. AUCn~ (+SD) 11073.1 (5:2991.1) 10976.1(5:3537.9) N.S. ttA (hrs) (ng ml-l) (_+SD) 7.5(5:2.1) [ 7.7(+1.6) N.S. After a single oral dosage of Lansoprazole 30 mg there were not significant differences in the pharmacokinetie parameters of Lansoprazole and its metabolites in plasma and urine between patients in Child-Campbell's A class with respect those in B/C class. CONCLUSIONS. 1) Although in cirrhotics the Lansoprazole t½ is about seven fold longer when compared with healthy volunteers (Eur. J. Pharmaeol. 1993;45:367), the degree of liver function impairment does not substaraially alter the Lansoprazole pharmacokinetic parameters in cirrhoties with different severity of liver disease. 2) There is not the need for Lansoprazole dosage adjustment in patients with liver cirrhosis and different degree of liver function derangement.
• ETHANOL-INDUCED CHANGES IN GASTRIC MUCUS GL¥COPROTEIN GLYCOSYLATION IN GOLGI. A. Slomianv, S. Sano and B.L. Slomiany. Res. Ctr., UMDNJ, Newark, NJ 07103. Ethanol-induced damage of gastric mucosa is the consequence of its action at various levels of cellular functions, expressed in transcription, translation, transport, and intracellular modification. The aim of this study was to d e t e r m i n e w h e t h e r p r o d u c t i o n of m o d i f i e d mucus glycoprotein is linked to changes in apomucin or is f u r t h e r compounded by ethanol affecting posttranslational glycosylation. The in vitro systems of purified Golgi preparation from gastric mucosa and glycosylation buffer containing UDPGlc, UDP-Gal, UDP-GIcNAc, ATP-activated cytosol, and GTP or G T P F S w e r e a s s e m b l e d with 0 - 1 2 0 m M ethanol. The glycosylation was conducted for 15, 30 and 60 min, and quantitated by ELISA assay of digoxigenin reactive glycoproteins. The standardization of the assay was performed with fetuin and c r e a t i n e kinase, as p o s i t i v e and negative substrates, respective!y. In control samples, when vesicular transport was blocked with G T P ~ S , the g l y c o s y l a t i o n i n c r e a s e d in a time dependent manner, and after lh, increased by 6875%. In samples containing ethanol, the glycosylation was inhibited by 66% at 30 min with no further change in glycosylation in the next 30 min of incubation. The studies provide direct evidence that ethanol induces synthesis of mucin with modified carbohydrate substitution. The results also suggest that ethanol causes changes in glycosylation of other proteins which may have p r o f o u n d c o n s e q u e n c e s in c a r b o h y d r a t e s p e c i f i c immunological and inflammatory responses in chronic alcoholism. Supported by NIH, NIAAA grant #AA05858-13.
Esophageal, Gastric, and Duodenal Disorders
A221
• A COMPARISON OF CULTURE, HISTOLOGY, AND 13CUREA BREATH TESTS FOR DETECTION OF 14. PYLORI. N. Slepman, S. Cox, C. Olson. Abbott Laboratories, Abbott Park, IL. Three diagnostic techniques for detecting H. pyloriwere employed in four large, well-controlled, treatment studies. Cultures (Cx), histology x), and 13C-urea breath (UBT) tests were used to assess • pylori (Hp) status in multicanter US and European studies conducted in 13 countries in patients with duodenal ulcers and Hp infection. The pretreatment and 4-6 week follow-up results are displayed below:
~
4-6 Week Folfow.-uD Histology
Histology UBT negative positive total
neg 47 6 53
pos 67 708 775
total 114 714 828
neg 237 8 245
pos 41 339 380
total 278 347 625
Culture negative positive total
53 2 55
133 657 790
186 659 845
239 6 245
70 319 389
309 325 634
The sensitivities for UBT and Cx using Hx as the gold standard were 91% and 83% at pretreatment and 89% and 82% at 4-6 weeks respectively. The US and European results were similar when comparing Cx versus Hx; however, the UBT was considerably more sensitive in the European studies than in the US (98% compared to 86% in the US pretreatment). The results from these studies suggest Hx was the most sensitive test for detecting H. pylori. Cx is useful for verifying positive results but is limited because of the number of false-negatives due to the asymmetric distribution of H. pyloriin the mucosa and the difficulty in transporting and culturing the organism. The UBT proved useful in the European studies but a number of false-negatives in the US studies indicates the need for standardization.
ENHANCEMENT IN GASTRIC MUCOSAL LAMININ RECEPTOR EXPRESSION WITH ULCER HEALING BY SUCRALFATE. B.L. Slomianv. J. Piotrowski, S. Sano and A. Slomiany. Res. Ctr., UMDNJ, Newark, NJ 07103. The i n t e g r i t y of the e p i t h e l i a l p e r i m e t e r of g a s t r i c m u c o s a l d e f e n s e is m a i n t a i n e d t h r o u g h specific interaction of the e p i t h e l i a l cell surface integrin receptors with adhesive proteins of the extracellular matrix. This interaction is considered of s i g n i f i c a n c e to a v a r i e t y of processes associated with cellular proliferation and tissue repair involving cell migration to the site of damage. In this study, we assessed the effect of a n t i u l c e r agent, sucralfate, on the e x p r e s s i o n of m u c o s a l laminin r e c e p t o r d u r i n g chronic ulcer healing. Groups of rats with acetic acid-induced chronic gastric ulcers were treated twice daily for 20 consecutive days either with sucralfate at 100mg/kg or placebo, and then at d i f f e r e n t stages used for the q u a n t i t a t i o n of g a s t r i c m u c o s a l l a m i n i n receptor. The assays revealed that the ulcer healing was accompanied by an increase in m u c o s a l e x p r e s s i o n of l a m i n i n receptor. A 1.9-fold increase in the receptor e x p r e s s i o n o c c u r r e d by 3rd day f o l l o w i n g the development of ulcer and reached a maximum of 8.6fold increase by the 14th day when the ulcer was essentially healed. Accelerated ulcer healing (8 days) with sucralfate treatment was accompanied by a s i g n i f i c a n t e v a l u a t i o n in laminin r e c e p t o r expression. In c o m p a r i s o n to the controls, s u c r a l f a t e evoked a 2 . 8 - f o l d i n c r e a s e in the laminin receptor expression by the 3rd day of treatment, reached a maximum of 3.1-fold the 7th day of treatment, and remained elevated even after 20 days of treatment. The findings attest to the importance of laminin receptor expression in the sustenance of proliferative activities of gastric mucosa essential for ulcer healing, and show that sucralfate possesses the ability to initiate and promote these events.