YALE JOURNAL OF BIOLOGY AND MEDICINE 69 (1996), pp. 203-209.
`Copyright © 1997. All rights reserved.
`
`Interaction of Proton Pump Inhibitors with Cytochromes P450:
`Consequences for Drug Interactions
`Urs A. Meyera
`Department ofPharmacology, Biozentrum of the University ofBasel, Basel, Switzerland
`(Received March 8, 1996; accepted May 15, 1996)
`
`Omeprazole, lansoprazole and pantoprazole are metabolized by several human
`cytochromes P450, most prominently by CYP2C19 and CYP3A4. Only panto-
`prazole is also metabolized by a sulfotransferase. Differences in the quantitative
`contribution of these enzymes and in the relative affinities of the substrates
`explain some of the observed interactions with carbamazepin, diazepam, pheny-
`toin and theophylline and of the impact of the CYP2C19 (mephenytoin) genet-
`ic polymorphism. Of these drugs, pantoprazole has the lowest potential for
`interactions, both in vitro and in human volunteer studies.
`
`INTRODUCTION
`The proton pump inhibitors (PPIs)b omeprazole, pantoprazole and lansoprazole are
`substituted benzimidazole sulfoxides with similar dose-efficacy profiles. Elimination of
`these drugs occurs almost entirely by rapid metabolism to inactive or less active metabo-
`lites, so that virtually no unchanged drug is excreted in urine and feces. The clearances of
`PPIs are between 0.1 and 0.5 1/h/kg-body-weight and the plasma half-lives range from 0.3
`to 2.2 hr [1-4]. Drug metabolism is subject to genetic and environmental variation, which
`is a frequent cause of patient-to-patient differences in drug effects. The differences in the
`metabolism of these drugs, therefore, may favorably or unfavorably affect the potential for
`interactions, enzyme induction and genetically polymorphic metabolism. On the other
`hand, it is well known that the inhibitory effect of these drugs on acid secretion persists
`for a long time, in spite of their rapid elimination.
`METABOLISM OF OMEPRAZOLE, LANSOPRAZOLE AND PANTOPRAZOLE
`Omeprazole
`Omeprazole remains the most extensively studied of the PPIs in regard to its metab-
`olism (Figure 1) [5, 6]. Omeprazole is primarily metabolized by aliphatic hydroxylation
`of the pyridinyl methyl group to hydroxy-omeprazole and by oxidation of the sulfoxide
`group to form omeprazole sulfone. Both metabolites are further metabolized to the
`hydroxysulfone. In vitro studies in human liver mircrosomes have also revealed some par-
`ticipation of CYP2C19, CYP3A and CYP2D6 in the formation of secondary and minor
`metabolites [6]. Two well-known cytochromes P450, CYP2C19 (S-mephenytoin hydrox-
`ylase) and CYP3A4 (nifedipine oxidase), catalyze these reactions. CYP2C19 exhibits a
`significant genetic polymorphism, and poor metabolizers of S-mephenytoin are also poor
`metabolizers of omeprazole [7-10] (see below).
`
`aTo whom all correspondence should be sent: Urs A. Meyer, Department of Pharmacology,
`Biozentrum of the University of Basel, Klingelbergstr. 70, CH-4056 Basel, Switzerland.
`Tel: 41-61-267-22-20; Fax: 41-61-267-22-08; E-mail: meyer2@ubaclu.unibas.ch.
`bAbbreviations: PPI, proton pump inhibitor; PM, poor metabolizer; EM, extensive metabolizer.
`
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`204
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`Meyer:
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`Metabolism ofproton pump inhibitors
`
`OMEPRAZOLE
`
`OCH3
`
`ICYP2C1 9
`
`HOH2C -
`Hydroxyomeprazole
`
`I CYP3A4>\
`
`0
`- S-and-S-
`11
`0
`Omeprazole sulfone
`and - sulfide
`CYP2C19 |
`I
`
`Omeprazole hydroxysulfone
`Figure 1. Major metabolic pathways of omeprazole and the enzymes involved. The size of the
`arrows approximates the overall importance of the pathway for elimination.
`
`LANSOPRAZOLE
`
`OCH2 CF3
`
`CYP2C[ 9?
`CYP3A4? 1
`
`-OH
`Hydroxylansoprazole
`
`(
`
`ICYP3A41
`
`01
`
`1
`- S-and-S-
`I'
`0
`Sulfite
`© Sulfone
`Figure 2. Major metabolic pathways of lansoprazole.
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`Meyer:
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`Metabolism ofproton pump inhibitors
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`205
`
`PANTOPRAZOLE
`
`,OCF2 H
`
`0
`-S-and-S-
`11
`0
`Sulfone
`
`Sulfide
`
`-OH
`Hydroxypantoprazole
`Sulfotransferase
`
`OSO3H (M2)
`Pantoprazole sulfate
`ICYP3A4?I \
`
`01
`
`1
`-S-and-S-
`11
`0
`(M3)
`(Ml)
`Figure 3. Major metabolic pathways of pantoprazole. Ml, M2 and M3 are the major metabolites
`detected in serum.
`
`Lansoprazole
`The major metabolic pathway of lansoprazole involves the formation of lansoprazole
`sulfone from the sulfoxide group (Figure 2). Lansoprazole sulfone is also the main
`metabolite present in serum. Hydroxylansoprazole is also formed, but the hydroxylation
`occurs at a different position (carbon 5 of the benzimidazole moiety) than for omeprazol
`(5-methyl carbon of the pyridinyl group). Studies with human liver microsomes and
`human hepatocytes in culture [1] indicate that, as with omeprazole, CYP3A4 is the major
`enzyme involved in the sulfone formation. However, the enzymes catalyzing the hydrox-
`ylation are less clearly identified and contributions of the cytochromes CYP3A4,
`CYP2C 18, CYP2C19 and others are suspected [ 1].
`Pantoprazole
`Pantoprazole (Figure 3) is also completely metabolized in the liver. It undergoes 0-
`demethylation by CYP2C19, which is followed by sulfate conjugation and some sulfone
`or sulfide formation, either by oxidation or reduction of the sulfoxide group [3, 4]. Recent
`in vivo and in vitro studies in human liver microsomes suggest that in addition to a cytoso-
`lic sulfotransferase, CYP2C19 and CYP3A4 affect the clearance of pantoprazole, i.e.,
`poor metabolizers of pantoprazole were also poor metabolizers of mephenytoin (Table 1,
`W.A. Simon, unpublished data). The same studies suggest that additional enzymes such
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`Meyer:
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`Metabolism ofproton pump inhibitors
`
`as CYP2C9 and CYP2D6 may contribute in a minor way to some of the reactions involved
`in the metabolism of pantoprazole.
`In summary, CYP2C19 and CYP3A4 (and in the case of pantoprazole a sulfotrans-
`ferase) are sequentially and alternatively involved in the metabolism of these drugs.
`However, the affinities of these enzymes for the different substrates and metabolites
`apparently vary remarkably. CYP2C 19 and CYP3A4 are well-studied human drug-metab-
`olizing enzymes and their substrates, inhibitors and inducers have been extensively
`reviewed [12, 131.
`ROLE OF THE CYP2C19 POLYMORPHISM FOR THE KINETICS OF PPI'S
`CYP2C19 or S-mephenytoin 4'-hydroxylase manifests a common genetic polymor-
`phism [14]. Two mutations, ml and m2, of the CYP2C19 gene have recently been demon-
`strated to cause loss of function alleles of this enzyme [15, 16]. Homozygous carriers of
`the mutation, thus, completely lack CYP2C19 enzyme and are so-called poor metaboliz-
`ers (PMs) of mephenytoin. These PMs have an up to 10-fold higher value of the area under
`the plasma concentration-time curve of omeprazole [7, 8, 17-19] as compared to extensive
`metabolizers. 2.5 to 6 percent of Caucasians and up to 30 percent of Oriental individuals
`are PMs [20]. During treatment with 40 mg/d omeprazole, approximately 80 percent of
`omeprazole clearance can be attributed to CYP2C19. When the dose is increased,
`CYP2C19 becomes limiting, and non-linear saturation kinetics may occur. Thus, at high
`doses, the kinetic parameter in EMs is shifted toward values observed in PMs who do not
`have a CYP2C19 enzyme. For omeprazole, at least, CYP3A4 appears to function as a
`high-capacity enzyme and prevents accumulation of very high omeprazole concentrations.
`Under these condition, CYP3A4 may become the major target of drug interaction. Similar
`studies have not been done for lansoprazole and pantoprazole, but as already discussed,
`CYP2C19 also plays a role in the metabolism of these drugs. PMs of mephenytoin were
`also PMs of pantoprazole (Table 1), and lansoprazole was shown in in vitro studies to be
`in part metabolized by CYP2C19.
`The relevance of the polymorphism for the efficacy and safety of acid inhibitory ther-
`apy by PPI's has not been evaluated. Chang et al. [18] reported higher gastrin levels in
`PMs after eight daily doses (20 mg) of omeprazole in PMs as compared to EMs, but no
`studies on acid secretion are yet available. This would be of particular importance in pop-
`ulations with a high percentage of PMs of mephenytoin. Moreover, gastrin levels were
`also higher in heterozygous carriers of a mutant alleles of CYP2C19. This finding sug-
`gests that approximately 60 percent of Orientals (including the homozygous and het-
`erozygous carriers of CYP2C19 mutant alleles) may have a slower metabolism of
`CYP2C 19 substrates than the majority of Caucasians.
`INDUCTION OF DRUG-METABOLISM BY PPI'S
`Omeprazole and lansoprazole induce the synthesis of CYPlAl and CYP1A2 [21].
`For omeprazole, induction of CYPlA enzymes has been demonstrated in biopsies of
`
`Table 1. Plasma half lives (h + S.D.) of omeprazole and pantoprazole in extensive
`metabolizers and poor metabolizers of mephenytoin. The phenotype for S-mepheny-
`toin hydroxylation was determined by the urinary S/R enantiomeric ratio.
`Omeprazole*
`Pantoprazole**
`0.69 + 0.41 (6)t
`Extensive metabolizers
`1.3 + 0.9 (11)
`2.30 + 0.44 (6)
`Poor metabolizers
`7.6 + 1.1 (4) (range 6.2-9)
`*Data from [8]. **Data from Byk Gulden, Konstanz, Germany. tNumber of volunteers.
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`Metabolism ofproton pump inhibitors
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`207
`
`human liver [21] and gut [22]. This effect has also been demonstrated in vivo in human
`volunteers by increased N3-demethylation of caffeine after omeprazole administration
`[24, 25] or increased clearance of theophylline after lansoprazole treatment [26]. In
`human hepatocyte cultures [27], CYP3A4 also was induced by omeprazole and its sul-
`fone, and by lansoprazole. The induction effect is concentration-dependent and, thus,
`occurs at lower doses in poor metabolizers of mephenytoin. The molecular mechanism of
`the induction of CYPIA1/2 and CYP3A4 by these drugs is not exactly known [28, 29].
`These observations have generated a debate on the risk of induced P450s for carcinogen-
`esis, since both CYPlAl and CYP3A4 can activate or inactivate procarcinogens. For
`some procarcinogens, induction can be an advantage, for others a disadvantage. Lack of
`induction of antipyrine, caffeine and theophylline clearance by pantoprazole suggests that
`this drug has little or no potential for induction [30, 31].
`DRUG INTERACTIONS
`PPIs interact with cytochromes P450 not only as substrates, but also as competitive
`inhibitors and inducers. Omeprazole inhibits the clearance of diazepam by 26 to 54 per-
`cent [32, 33], and this inhibition is more apparent in individuals of the mephenytoin exten-
`sive metabolizer phenotype (EMs), indicating that at therapeutic concentrations omepra-
`zole and diazepam compete for the same site on CYP2C19. Neither lansoprazole [34] nor
`pantoprazole [35] seem to affect diazepam kinetics. A decrease in the clearance of pheny-
`toin [36] and carbamazepin [37] points to interaction of omeprazole with other
`cytochromes P450, presumably of the CYP2C9 subfamily. Lansoprazole and pantoprazole
`
`Table 2. Interactions of PPIs with other drugs.
`
`Drug tested
`
`Theophylline
`Caffeine
`
`Phenytoin
`Warfarin
`Carbamazepin
`Diclofenac
`Phenprocoumon
`
`Mephenytoin
`Diazepam
`
`Debrisoquine
`Propanalol
`Metoprolol
`
`Nifedipin
`Cyclosporine
`Lidocaine
`Quinidine
`Contraceptives
`
`Major P450
`
`Omeprazole
`
`CYP1A2
`CYPlA2
`
`CYP2C9
`CYP2C9
`CYP2C8
`CYP2C9
`?
`
`CYP2C19
`CYP2Cl9
`
`CYP2D6
`CYP2D6 + others
`CYP2D6
`
`CYP3A4
`CYP3A4
`CYP3A4
`CYP3A4
`CYP3A4
`
`No IA
`IM
`JkCI
`(4ICl)
`ICI
`NT
`NT
`
`JtM
`JICI
`No IA
`No IA
`No IA
`(JkCl?)
`No IA
`No IA
`No IA
`NT
`
`Lansoperazole
`(TCI)
`NT
`
`No IA
`No IA
`DC NT
`NT
`NT
`
`NT
`No IA
`
`NT
`No IA
`NT
`
`NT
`NT
`NT
`NT
`Eff. on ovul.?
`
`Pantoprazole
`
`No IA
`No IA
`
`No IA
`No IA
`No IA
`No IA
`No IA
`
`No IA
`No IA
`
`No IA
`NT
`NT
`
`No IA
`NT
`NT
`NT
`No IA
`
`CYP2E1
`CYP3A/2C/1A2
`
`NT
`Alcohol
`NT
`No IA
`(1Cl)
`(TCl)
`Antipyrine
`No IA
`renal excr.
`Methotrexate
`NT
`NT
`(I absorption)
`Absorption
`Digoxin
`NT
`No IA
`I absorption
`Absorption
`Bismuth
`NT
`NT
`IA = interaction; Cl = clearance; M = metabolism; NT = not tested; (= of questionable signifi-
`cance.
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`Meyer:
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`apparently do not interact with CYP2C19 and other CYP2C substrates. The induction of
`CYP1A2 by omeprazole and lansoprazole is reflected by the increased clearance of caf-
`feine [24, 25] and theophylline [26], respectively. No clinically relevant interactions of the
`three drugs with most CYP3A4 substrates have been observed. Extensive studies with pan-
`toprazole showed this drug to have the lowest potential of these three drugs for metabolic
`interactions in vitro and in vivo. The present data-base on interactions is summarized in
`Table 2 and References 1-4, 30, and 38.
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