Prevacid
Pharmacokinetic differences between the enantiomers of lansoprazole and its metabolite, 5-hydroxylansoprazole, in relation to CYP2C19 genotypes.

Miura M, Tada H, Yasui-Furukori N, Uno T, Sugawara K, Tateishi T, Suzuki T.

Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, 010-8543, Akita, Japan.

OBJECTIVE: The purpose of this study was to elucidate the pharmacokinetics of each enantiomer of lansoprazole and 5-hydroxylansoprazole in three different CYP2C19 genotype groups of Japanese subjects. METHODS: Healthy subjects ( n=18), of whom 6 were homozygous extensive metabolizers (homEMs), 6 were heterozygous extensive metabolizers (hetEMs) and 6 were poor metabolizers (PMs), participated in the study. After a single oral dose of 60 mg of racemic lansoprazole, the plasma concentrations of the lansoprazole enantiomers, 5-hydroxylansoprazole enantiomers and lansoprazole sulfone were measured for 24 h post-dose. RESULTS: The plasma concentrations of ( R)-lansoprazole were remarkably higher in all three CYP2C19 genotype groups than those of the corresponding ( S)-enantiomer. The mean maximum plasma concentration ( C(max)) of ( S)-lansoprazole differed significantly among the three groups, whereas there was no difference for the ( R)-enantiomer. The relative area under the plasma concentration (AUC) ratios of ( R)- and ( S)-lansoprazole in the homEMs, hetEMs, and PMs were 1:1.5:4.0 and 1:1.8:7.4, respectively. Yet, the relative AUC ratios of 5-hydroxylansoprazole to lansoprazole for the ( R)- and ( S)-enantiomers in the homEMs, hetEMs, and PMs were almost the same (1:0.73:0.12 and 1:0.77:0.13, respectively). However, the AUC ratios of the ( S)-enantiomer were 13-fold greater for the three CYP2C19 genotypes than those of the corresponding ( R)-enantiomer. CONCLUSIONS: The magnitude of the contribution of CYP2C19 to the 5-hydroxylation of ( S)-lansoprazole was greater than that of the ( R)-enantiomer. The R/S ratios for the AUC of lansoprazole for the homEMs, hetEMs and PMs were 12.7, 8.5 and 5.8, respectively, suggesting a significant effect of CYP2C19 polymorphisms on the stereoselective disposition of lansoprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15448955&dopt=Abstract lansoprazole Prevacid



Prevacid
Serum cholinesterase inhibition by omeprazole and lansoprazole.

Mequid S, Ramzan I.

Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia.

Omeprazole inhibited human and rat serum cholinesterase by approximately 5 to 60% over the 0.5 to 50 mg/L (1.4-140 microM) concentration range. In contrast lansoprazole only produced 20-30% inhibition at the highest concentration of 10 mg/L (29 microM). Thus omeprazole but not lansoprazole is likely to potentiate the effect of succinylcholine at human clinical concentrations by inhibiting its hydrolysis in vivo by serum cholinesterases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15497763&dopt=Abstract lansoprazole Prevacid



Prevacid
Evaluation of fast disintegrating lansoprazole tablet in human subjects.

Iwasaki K, Yoshikawa Y, Shibata N, Takada K, Sakurai Y, Takagi N, Irie S, Nakamura K.

Department of Pharmacokinetics, Kyoto Pharmaceutical University, Japan. Iwasaki_Kouji takeda.co.jp

Fast disintegrating lansoprazole tablet (LFDT) has been developed as a multiple unit formulation and evaluated using human subjects as compared to the conventional lansoprazole (LPZ) capsule containing enteric coated granules. Twelve healthy male volunteers, who were confirmed as extensive metabolizers (EMs) based on the plasma levels of LPZ sulphone metabolite, were enrolled into the study and genotype of CYP2C19 was confirmed. They kept 30 mg LFDT in their mouths for 2 min and the saliva was recovered without swallow. Eight subjects did not show LPZ in their serum after intake. Although LPZ was detected in 4 subjects' serum, their concentrations were less than 5 ng/mL. LPZ was thought to be not absorbed from the oral cavity. LFDT was orally administered to 12 healthy male EMs at two doses, 15 mg and 30 mg, and serum LPZ concentrations were measured. The mean C(max) and AUC(0-24) were 474.1+/-254.0 ng/mL and 1105.3+/-1101.4 ng.h/mL (15 mg) and 992.8+/-384.3 ng/mL and 2216.5+/-1270.1 ng.h/mL (30 mg). By comparing to that obtained after oral administration of the same doses of LPZ capsule, serum LPZ concentration vs. time curve was almost the same level, i.e., C(max) and AUC(0-24) did not have significant differences. From these results, LFDT has been shown to be equivalent to LPZ capsule and will show the same acid suppressing effects in the clinical situation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15499190&dopt=Abstract lansoprazole Prevacid



Prevacid
Lansoprazole enantiomer activates human liver microsomal cyp2c9 catalytic activity in a stereospecific and substrate-specific manner.

Liu KH, Kim MJ, Jung WM, Kang W, Cha IJ, Shin JG.

Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine and Clinical Pharmacology Center, Busan Paik Hospital, Korea.

We recently proposed a possible stereoselective activation by lansoprazole of CYP2C9-catalyzed tolbutamide hydroxylation, as well as stereoselective inhibition of several cytochrome P450 (P450) isoforms. This study evaluated the effects of lansoprazole enantiomers on CYP2C9 activity in vitro, using several probe substrates. For tolbutamide 4-methylhydroxylation and phenytoin 4-hydroxylation, R-lansoprazole was an activator (140 and 550% of control at 100 microM R-lansoprazole, EC50 values of 19.9 and 30.2 microM, respectively). R-Lansoprazole-mediated activation of the formation of 4-hydroxyphenytoin was also seen with recombinant human CYP2C9. R-Lansoprazole increased the Michaelis-Menten-derived V(max) of phenytoin 4-hydroxylation from 0.024 to 0.121 pmol/min/pmol P450, and lowered its K(m) from 20.5 to 15.0 microM, suggesting that R-lansoprazole activates CYP2C9-mediated phenytoin metabolism without displacing phenytoin from the active site. Kinetic parameters were also estimated using the two-site binding equation, with alpha values <1 and beta values >1, indicative of activation. Additionally, phenytoin at 10 to 200 microM had no reciprocal effect on the hydroxylation of R-lansoprazole. Meanwhile, R-lansoprazole had no activation effect on diclofenac and S-warfarin metabolism in the incubation study using both recombinant CYP2C9 and human liver microsomes. These substrate-dependent activation effects suggest that phenytoin has a different binding orientation compared with diclofenac and S-warfarin. Overall, these results suggest that R-lansoprazole activates CYP2C9 in a stereospecific and substrate-specific manner, possibly by binding within the active site and inducing positive cooperativity. This is the first report to describe stereoselective activation of this cytochrome P450 isoform.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15537834&dopt=Abstract lansoprazole Prevacid



Prevacid
Adverse reactions during imatinib and lansoprazole treatment in gastrointestinal stromal tumors.

Severino G, Chillotti C, De Lisa R, Del Zompo M, Ardau R.

Section of Clinical Pharmacology, Department of Neurosciences, B.B. Brodie, University of Cagliari, Cagliari, Italy.

OBJECTIVE: To report the case of a patient affected by gastrointestinal stromal tumors (GIST) who developed cutaneous adverse drug reactions during treatment with imatinib and lansoprazole. CASE SUMMARY: After 2 months of treatment with imatinib 400 mg/day, a 60-year-old white female affected by GIST developed bilateral palpebral edema with hyperemic conjunctivae and labial edema when lansoprazole 15 mg/day was introduced to treat dyspeptic symptomatology. Treatment was discontinued, and on reintroduction of both drugs, the patient developed Stevens-Johnson syndrome. Two months later, generalized cutaneous reactions appeared immediately following reintroduction of low-dose imatinib with corticosteroid plus lansoprazole treatment. After discontinuation of all drugs, with the exception of the corticosteroid, the progression of cutaneous lesions stopped. DISCUSSION: The use of imatinib is commonly associated with a high dose-dependent rate of rash and edema. Several cases of Stevens-Johnson syndrome have also been described, although not in patients affected by GIST. Severe skin reactions have been reported for lansoprazole including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Applying Naranjo's algorithm, the adverse events were considered possible due to imatinib and probable due to lansoprazole. CONCLUSIONS: On the basis of the data reported, we conclude that the adverse reactions described may be attributed to either drug alone. However, combined use of drugs may increase the risk of onset of these adverse reactions due to a potential drug interaction involving CYP3A4.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15546944&dopt=Abstract lansoprazole Prevacid