Prevacid
Effects of lansoprazole on pharmacokinetics and metabolism of theophylline.

Kokufu T, Ihara N, Sugioka N, Koyama H, Ohta T, Mori S, Nakajima K.

Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Japan.

The effect of the new substituted benzimidizole proton pump inhibitor, lansoprazole, on pharmacokinetics and metabolism of theophylline has been studied in healthy adults given oral lansoprazole 30 mg once daily for 11 days. On Days 4 and 11 of 300 mg aminophylline was simultaneously administered orally and blood samples for theophylline analysis were taken over 24 h. Urine samples were collected for up to 24 h and were assayed for theophylline and its major metabolites 1,3-dimethyluric acid (1,3-DMU), 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX). The pharmacokinetic parameters of theophylline were determined, and the urinary recovery of unchanged theophylline and its major metabolites were calculated. After administration of lansoprazole for 4 days, no significant alteration in the terminal elimination half-life (t1/2beta) or the mean resistance time (MRT) was detected. However, there was a significant decrease of about 13% in the area under the plasma concentration-time curve (AUC) and a significant increase of about 19% in the apparent clearance (CLapp). Lansoprazole treatment for 11 days caused a significant decrease of approximately 12% in t1/2beta and about 10% in the MRT of theophylline, although neither AUC nor CLapp showed a significant alteration. The excretion of 3-MX in the urine was significantly increased by about 20% after lansoprazole treatment for 4 and 11 days, although there was no significant alteration in the excretion of unchanged theophylline, 1,3-DMU or 1-MU. The results indicate that repeated administration of lansoprazole to humans induces the hepatic microsomal P-450-dependent drug oxidation system that mediates N-1-demethylation of theophylline, consequently increasing its metabolism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8641328&dopt=Abstract lansoprazole Prevacid



Prevacid
Capsaicin-sensitive sensory neurons are involved in bicarbonate secretion induced by lansoprazole, a proton pump inhibitor, in rats.

Inada I, Satoh H.

Pharmaceutical Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.

Lansoprazole, a proton pump inhibitor, exerts prominent antiulcer activity via both antisecretory and mucosal protective actions. Although the antisecretory action has been explained by inactivation of (H+, K+)-ATPase in parietal cells, the mode of mucosal protective action remains to be elucidated. In the present study, the effect of lansoprazole on duodenal bicarbonate secretion was studied in anesthetized rats to clarify the mode of the mucosal protective action. Lansoprazole (0.1 mM) applied topically to the duodenum significantly (P < 0.01) increased bicarbonate secretion by 0.36 +/- 0.11 microeq/15 min (21 +/- 5%) compared with the value in the vehicle control. Topical administration of capsaicin (10 mg/ml) in the duodenum and intravenous infusion of vasoactive intestinal peptide (10 micrograms/kg/hr) increased bicarbonate secretion. Five-minute perfusion of the duodenal loop with 100 mM HCl increased bicarbonate secretion. Administration of lansoprazole (0.3 and 1 mg/kg, intravenously) 60 min before luminal acidification enhanced the acid-induced bicarbonate secretion dose-dependently and significantly (P < 0.01). In the capsaicin-pretreated rats, the effects of lansoprazole on basal and acid-induced bicarbonate secretion were significantly (P < 0.05) decreased compared with that of control group. These results indicate that lansoprazole increases basal and acid-induced bicarbonate secretion in the duodenum in rats and that capsaicin-sensitive sensory neurons may be involved in the mode of action for these effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8674400&dopt=Abstract lansoprazole Prevacid



Prevacid
Influence of H2-receptor- and proton pump inhibitors on some functions of the oxydative and conjugative drug metabolism.

Scheuch E, Walter R, Hadasova E, Amon I, Siegmund W.

Department of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany.

There are numerous investigations describing the influence of histamine H2-receptor antagonists and proton pump inhibitors on cytochrome P450-mediated hepatic oxydative and conjugative drug metabolizing enzymes. The aim of this study was to investigate the influence of the H2-receptor blockers cimetidine, ranitidine, famotidine, nizatidine and of the proton pump inhibitors omeprazole and lansoprazole on the acetylation capacity and on different microsomal monooxygenases of the rat liver. The experiments were performed in two randomized studies with male Wistar rats after a 7-day pretreatment of the animals with antisecretory, equipotent doses of the investigational products. The activities of the arylamine N-acetyltransferase (NAT) and the microsomal enzymes were determined in vitro. Cimetidine and ranitidine decreased the activity of NAT significantly, no effect on this enzyme was observed after nizatidine. Small doses of famotidine tended to lower, high doses of famotidine tended to enhance the NAT activity. The proton pump inhibitor omeprazole significantly increased the NAT activity, lansoprazole evoked a small increase of the enzyme activity. Ethyl-resorufin O-deethylase (EROD) and penthlresorufin O-depentylase (PROD) were sensitive to cimetidine, ranitidine and famotidine. Only omeprazole and lansoprazole treatment inhibited the detromethorphan O-demethylase (DXDM) activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8774841&dopt=Abstract lansoprazole Prevacid



Prevacid
Pharmacokinetic-pharmacodynamic study of oral lansoprazole in children.

Tran A, Rey E, Pons G, Pariente-Khayat A, D'Athis P, Sallerin V, Dupont C.

Pharmacologie Perinatale et Pediatrique, Gastroenterologie Pediatrique, Universite Rene Descartes, Hopital Saint-Vincent de Paul, 82 Avenue Denfert-Rochereau, Assistance Publique-Hopitaux de Paris, 75674 Paris, France.

OBJECTIVE: We investigated the pharmacokinetics, pharmacodynamics, and tolerability of lansoprazole in children after single and multiple administrations. METHODS: Forty children (age range, 18 days-14 years) with gastric acid-related disorders entered an open study and received lansoprazole in a single dose of 17 mg. m(-2) (group A) or in multiple doses (17 mg. m(-2) per day) for 7 to 14 days (group B). Lansoprazole plasma concentrations were measured by HPLC. A 24-hour intragastric pH monitoring assessed the antisecretory effect. RESULTS: In group A, maximal concentration (C(max)) was 1023 +/- 775 (mg. L(-1))/(17 mg. m(-2)), time to reach C(max) was 1.8 +/- 0.8 hours, elimination half-life was 1.5 +/- 2.0 hours, area under the concentration-time curve from time zero to infinity [AUC(0-infinity)] was 3503 +/- 6025 (mg. L(-1). h)/(17 mg. m(-2)), apparent plasma clearance was 0.57 +/- 0.47 L. h(-1). kg(-1), and apparent volume of distribution was 0.61 +/- 0.36 L. kg(-1). In group B, C(max) was 750 +/- 511 (mg. L(-1))/(17 mg. m(-2)), time to reach C(max) was 1.8 +/- 1.1 hours, elimination half-life was 1.2 +/- 1.1 hours, AUC(0-infinity) was 2351 +/- 3691 (mg. L(-1). h)/(17 mg. m(-2)), apparent plasma clearance was 0.71 +/- 0.50 L. h(-1). kg(-1), and apparent volume of distribution was 0.9 +/- 0.7 L. kg(-1). No influence of age was shown on pharmacokinetic parameters in both groups. However, data suggested that elimination was reduced in neonates and higher in infants than in adults. The values for 24-hour percentage of time at gastric pH <4 and pH <3 were 61% +/- 21% and 51% +/- 21% (group A) and 47% +/- 24% and 37% +/- 21% (group B), respectively. In both groups the antisecretory effect decreased with age, and in group A it was positively correlated to C(max) and AUC(0-infinity). The mean gastrin serum concentration significantly increased (+31%) after 12.6 +/- 1.5 days of treatment. CONCLUSIONS: Lansoprazole was well tolerated in children. After a single oral dose of 30 mg per 1.73 m(2), there was a trend for the elimination to be higher in infants than in adults and the antisecretory effect appeared to be higher in infants younger than 6 months than in older children and adults.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12011821&dopt=Abstract lansoprazole Prevacid



Prevacid
Indomethacin-induced morphological changes in the rat gastric mucosa, with or without prior treatment with two proton pump inhibitors.

Morini G, Grandi D, Arcari ML, Bertaccini G.

Institute of Pharmacology, University of Parma, Italy.

BACKGROUND: The mechanisms responsible for the gastric ulcerogenic effect of indomethacin are unclear. The importance of basal acid secretion on morphological changes by indomethacin was investigated. METHODS: Gastric lesions were macroscopically evaluated 6 h after indomethacin, 20 mg/kg intragastrically, in rats pre-treated with omeprazole (10-100 mumol/kg intragastrically) or lansoprazole (3-30 mumol/kg intragastrically). Glandular mucosa was processed for light, scanning and transmission electron microscopy 3 and 6 h after indomethacin in rats pre-treated with omeprazole (100 mumol/kg) or lansoprazole (30 mumol/kg). RESULTS: After 3 h, indomethacin caused extensive vasocongestion, oedema in the subepithelial region and superficial erosions. After 6 h, deeply extending focal necrosis involved 11% of the tissue. Leukocyte margination was occasionally seen at 3 h and consistently present at 6 h. Only at 6 h were endothelial cells altered. In rats pre-treated with omeprazole (100 mumol/kg) or lansoprazole (30 mumol/kg) grossly visible lesions were prevented. Oedema, erosions and necrosis were absent. Vasocongestion, vascular leakage and leukocytic margination were seen both at 3 and 6 h while no major damage of endothelial cells was observed. CONCLUSION: Indomethacin appears primarily to alter microcirculation, and microcirculation damage is dependent on acid for the progression to haemorrhagic lesions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8824648&dopt=Abstract lansoprazole Prevacid