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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  Impaired acid secretion may affect drug absorption and may be consequent to corporal Heliocobacter pylori-gastritis, which may affect the absorption of orally administered drugs.

Aim  To focus on the evidence of impaired drug absorption associated with H. pylori infection.

Methods  Data sources were the systematic search of MEDLINE/EMBASE/SCOPUS databases (1980–April 2008) for English articles using the keywords: drug malabsorption/absorption, stomach, Helicobacter pylori, gastritis, gastric acid, gastric pH, hypochlorhydria, gastric hypoacidity. Study selection was made from 2099 retrieved articles, five studies were identified. Data were extracted from selected papers, investigated drugs, study type, main features of subjects, study design, intervention type and results were extracted.

Results  In all, five studies investigated impaired absorption of l-dopa, thyroxine and delavirdine in H. pylori infection. Eradication treatment led to 21–54% increase in l-dopa in Parkinon’s disease. Thyroxine requirement was higher in hypochlorhydric goitre with H. pylori-gastritis and thyrotropin levels decreased by 94% after treatment. In H. pylori- and HIV-positive hypochlorhydric subjects, delavirdine absorption increased by 57% with orange juice administration and by 150% after eradication.

Conclusions  A plausible mechanism of impaired drug absorption is decreased acid secretion in H. pylori-gastritis patients. Helicobacter pylori infection and hypochlorhydria should be considered in prescribing drugs the absorption of which is potentially affected by intragastric pH.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Gastrointestinal absorption is an important determinant that influences the efficacy of orally administered drugs and the multiple variables involved in the drug absorption process are not yet fully elucidated. Drug absorption may be influenced by specific characteristics of the drug itself, as molecular size and shape, solubility at absorption site, degree of ionization and lipid solubility of its ionized and non-ionized forms.1, 2 The pharmacokinetics of a drug may also be affected by physiological parameters of the stomach, such as gastric motility, the volume and pH of gastric secretion and modifications of gastric acidity.3

Helicobacter pylori infects about half the world population and causes a chronic inflammatory response of the gastric mucosa, which may lead to alterations in some physiological functions of the stomach.4 Indeed, H. pylori-induced inflammation of the gastric mucosa may affect gastric motility5, 6 and, in particular, H. pylori infection may induce a dysfunction in gastric myoelectrical and motor activity leading to alterations in gastric emptying.7, 8

Impaired gastric acid secretion is a common consequence of H. pylori-induced gastritis and the effect of H. pylori infection on gastric acid secretion depends on the severity and distribution of gastritis.9 In particular, corpus inflammation leads to a decreased acid secretory capacity and this may initially be due to functional inhibition of parietal cells by inflammation products.4, 10 The proinflammatory cytokine interleukin-1ß, a key mediator in H. pylori-associated disease, has been reported to inhibit gastric acid secretion in vitro and in vivo.11–13 The chronic inflammatory injury may lead to a permanent loss of parietal cells, resulting in gastric glands atrophy and hypochlorhydria.14, 15

Thus, it is reasonable that H. pylori infection may potentially affect the drug absorption process and, considering the high prevalence of H. pylori infection, its interference with drug absorption may have important clinical implications. In this systematic review, we aimed to focus on the evidence of impaired drug absorption associated with H. pylori infection.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Data sources and study identification

Search methods for identification of studies.  The search was conducted using QUOROM guidelines.16 The MEDLINE (via PubMed), EMBASE and SCOPUS databases were systematically searched using the following search criteria to identify relevant English-language papers published between 1980 and April 2008: drug malabsorption and drug absorption combined with stomach, H. pylori, gastritis, gastric acid, gastric pH, hypochlorhydria, gastric hypoacidity, gastric motility (by using AND constructions). Manual searches of reference lists from potentially relevant papers were performed to identify additional studies that may have been missed using the computer-assisted search strategy. The Cochrane Central Register of Controlled Trials was searched for other relevant reports.

Inclusion criteria and types of studies.  We considered all relevant clinical studies performed on adult human subjects addressing the item of drug malabsorption associated with H. pylori infection, which were published between 1980 and April 2008. We considered as high quality studies randomized controlled trials, randomized crossover studies, prospective and retrospective cohort studies and case–control studies; as moderate quality studies cross-sectional studies and case series.17

Exclusion criteria.  Papers published in other than English language, case reports, meta-analyses and reviews were excluded from the present review.

Study selection and data extraction

All abstracts or titles identified by the electronic searches were independently scrutinized by two researchers. The reviewers checked whether inclusion and exclusion criteria were met and when uncertainty arose or when there were differences between the reviewers, the hard copies of papers were obtained and reviewed and disagreement was resolved by consensus.

Nonpertinent articles were discarded and a hard copy of all selected papers was obtained. The bibliographies of all relevant papers identified by computer-assisted searching were searched for additional studies for which a hard copy was obtained. Also in this case, eventual disagreement between reviewers was resolved by consensus.

From each selected paper, data considered as relevant, such as the author and the publication year, the name of the investigated drug, the study type, the main features of the studied subjects, the study design and the type of intervention, as well as the results of the study, were extracted.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Description of selected studies

Automatic searching from the electronic databases identified 2099 papers. After manually removing duplicates (= 1369) and discarding nonpertinent papers (= 726), we selected four studies which met the inclusion criteria and for which full text was obtained. Searching the reference lists of potential relevant articles and pertinent reviews, we identified another study for which we obtained the full text. Thus, a total of five studies were selected for review of the full paper:18–22 one was a randomized controlled trial,19 two were controlled crossover studies,18, 22 one was a case–control study20 and one was a case series.21 Four studies met the criteria for having a high weight rating and one for a moderate weight rating of clinical evidence.17

Overall, these five papers investigated the impaired absorption of three different drugs in association with H. pylori infection; these three drugs are used in three different medical specialties: l-dopa, the classical treatment of Parkinson’s disease,18, 19 thyroxine, a widely used therapy for thyroid disorders20 and delavirdine, an antiviral agent active against human immunodeficiency virus (HIV)-1.21, 22Table 1 summarizes the type of the drug, the type of the study and the weight rating of clinical evidence of the selected studies.

Table 1.   Absorption of investigated drugs in association with the presence of Helicobacter pylori infection
Author (year)Investigated drugStudy designSubjectsHelicobacter pylori positivityHypochlorhydriaInterventionOutcome measureEffect on drug absorption
  1. BAO, basal acid output; MAO, maximal acid output; AUC, area under the plasma concentration curve; HIV, human immunodeficiency virus; tx, treatment; pts, patients.

Pierantozzi et al. (2001)18l-DopaPlacebo-controlled crossover study6 Pts with Parkinson’s diseaseSerologyNot assessedEradication tx vs. placeboAUC of l-dopa 21% Increase after eradication treatment no variation after placebo
Pierantozzi et al. (2006)19l-DopaRCT34 Pts with Parkinson’s disease Serology, stool test, CP-test or cultureNot assessedEradication tx vs. antioxidant tx (allopurinol)AUC of l-dopa 54% Increase after eradication treatment no variation after antioxidant tx
Centanni et al. (2006)20ThyroxineCase–control study248 Pts with multinodular goitre treated with thryoxine: 113 with hypochlorhydria and 135 without gastric disordersHistology and/or serology Hypergastrinaemia and/or BAO and MAO after pentagastrin stimulationEradication tx in a subset of 11 pts; PPI tx (omeprazole) in subset of 10 ptsDaily requirement of thyroxine; thyrotropin level27% Increase in pts with hypchlorhydria 94% decrease after eradication tx 37% increase with omeprazole
Shelton et al. (2000)21DelavirdineCase series5 HIV-positive pts with spontaneous hypochlorhydriaSerologyIntragastric pH >3Eradication txAUC of delavirdine150% Increase after eradication tx
Shelton et al. (2003)22DelavirdineRandomized, crossover study21 HIV-positive subjects with and without spontaneous hypochlorhydriaSerologyHypochlorhydric pts (= 11): pH >3; Nonhypochlorhydric pts (= 10): pH <3Delavirdine + water vs. delavirdine + orange juice AUC of delavirdine47% Decrease in hypochlorhydric pts 57% increase after orange juice

Results of selected studies

As shown in Table 1, which synthesizes the main results of the five selected studies, there was a significant variation in study population and design as well as type of intervention. The sample size for most of the studies was small with four studies examining fewer than 50 patients.18, 19, 21, 22 Only one of the retrieved studies was placebo-controlled.18 In one study, pharmacokinetic data are not available and drug absorbtion was deduced by the daily requirement of thyroxine and/or the thyrotropin levels.20

In all selected studies, the presence of H. pylori infection was concomitant to the presence of other diseases: Parkinson’s disease,18, 19 multinodular goitre20 and HIV infection.21, 22 In three studies, the presence of H. pylori infection was assessed by serology only18, 21, 22 and in two studies, the assessment of H. pylori status was completed by histological examination of gastric biopsies.19, 20

Gastric acid secretion was assessed in only three studies,20–22 which included the measurement of fasting gastrin and/or gastric secretion studies after pentagastrin stimulation20 or the measurement of gastric pH by a consumable radiotelemetric device.21, 22 As regards the type of intervention, in three studies,18, 19, 21 the absorption of the drug was investigated before and after eradication treatment in all patients, in one study20 the effect of eradication therapy on drug absorption was evaluated only in a subset of patients22 and in two studies,20, 22 the absorption of the drug was investigated with respect to gastric acidity. Thus, in the selected studies, the study design addressed only in part the mechanisms of oral drug absorption.

The different types of intervention as well as the different presentation of data regarding the outcome of drug absorption in the individual studies as well as the low number of identified studies did not allow pooling of the outcome to create a summary measure and to perform statistical evaluation. The results of the selected studies are thus described separately for the different drugs.

l-Dopa.  We identified two studies performed by the same group of authors18, 19 in which the effect of H. pylori eradication treatment on the absorption of l-dopa was evaluated. l-Dopa is well established as the most effective drug in the symptomatic treatment of Parkinson’s disease.23 After the occasional observation of a consistent clinical improvement of wearing-off phenomenon in an advanced Parkinson’s disease patient immediately after the eradication of H. pylori, the effect of the eradication treatment on the pharmacokinetic and clinical response to l-dopa in patients with advanced Parkinson’s disease and a high IgG antibody titre against H. pylori was investigated.18 The preliminary data on six patients showed that eradication treatment led to a 21% increase in l-dopa plasma concentration with concomitant clinical benefit. The same authors confirmed their preliminary results in a randomized controlled trial19 conducted on 34 patients with Parkinson’s disease and histologically diagnosed active H. pylori-gastritis, who were randomized to receive either a 7-day course of eradication treatment (omeprazole, amoxicillin and clarithromycin) or an antioxidant treatment for 15 days (allopurinol) and were followed up for 3 months. Different from the antioxidant-treated patients, the eradication therapy group showed a 54% increase in l-dopa absorption, which was coupled with a significant improvement in clinical disability, whereas gastritis scores significantly decreased in line with better l-dopa pharmacokinetics. Interestingly, in two patients in whom the eradication therapy failed to cure H. pylori infection, neither the l-dopa pharmacokinetics nor the neurological symptoms improved.

The mechanism by which H. pylori may affect l-dopa absorption is still speculative. l-Dopa solubility is pH-sensitive24 and eradication-induced normalization of gastric acid secretion may have improved l-dopa absorption and clinical response.11, 25 Unfortunately, gastric acidity was not measured in this study; however, the similar antral and corporal gastritis scores suggest the presence of corporal gastritis and potential hypochlorhydria in a vast majority of the investigated Parkinson’s disease patients.

The association between impaired absorption of l-dopa and H. pylori-gastritis may be of epidemiological relevance because in the decade of maximal prevalence of Parkinson’s disease, a high incidence of H. pylori infection has been reported.23, 26 Thus, in elderly patients with Parkinson’s disease often characterized by poor response to l-dopa therapy,23 the H. pylori-related impairment of l-dopa absorption may be important and implicate the need of a specific diagnostic work-up to assess the presence of H. pylori-gastritis.

Thyroxine.  Thyroxine is a widely used drug in the treatment of patients with thyroid disease, mainly as replacement therapy for hypothyroidism27 and efficient absorption of oral thyroxine appears to be important to ensure optimal treament.28 We identified one recent case–control study,20 which addressed whether euthyroid multinodular goitre patients with H. pylori-gastritis and hypochlorhydria have an increased need for thyroxine: in particular, the study was performed on 113 goitre patients with hypochlorhydria (H. pylori-related atrophic and non-atrophic gastritis) and 135 goitre patients without any gastric disorders and showed that the daily thyroxine requirement was significantly (by 22–34%) higher in the hypochlorhydric group than in controls. Furthermore, the occurrence of H. pylori infection in a subset of patients led to an increase in the daily need for thyroxine which was nearly reversed on eradication treatment associated with a 94% decrease in thyrotropin levels. The authors concluded that conditions characterized by impaired acid secretion, as atrophic gastritis and H. pylori infection, required an increased daily dose of thyroxine, suggesting that normal gastric acid secretion is necessary for effective absorption of oral thyroxine. The role of acidic gastric pH for the correct thyroxine absorption was further supported in this study by the finding that omeprazole treatment in a subset of patients with heartburning was associated with an increased need for thyroxine, which was reversed to the previous need for the drug when omeprazole therapy was discontinued.

The mechanism by which thyroxine absorption is impaired in H. pylori-induced hypochlorhydria is not known, but it may be hypothesized that hypochlorhydria itself or the ammonia production characteristic of H. pylori infection may alter the ionization status and the conformational characteristics of the thyroxine molecule and thus its absorption efficiency.20

The implications of impaired absorption of thyroxine in subjects with H. pylori-related hypochlorhydria may be relevant. In Europe, thyroid diseases are frequent due to the presence of iodine deficiency and their prevalence can be estimated up to 15%.29, 30 A recent study has reported that thyroid disorder are associated in more than half (53%) of patients with H. pylori-related atrophic body gastritis.31 Thus, physicians should be aware that the increased need for thryoxine may be due to the presence of H. pylori-induced hypochlorhydria and specific diagnostic work-up to ascertain the presence of decreased gastric acid secretion and/or H. pylori-related gastritis may be beneficial in these cases.

Delavirdine.  We identified two studies conducted by the same group of authors21, 22 who evaluated the role of hypochlorhydria in the absorption of delavirdine in H. pylori-positive subjects with concomitant HIV-seropositivity. Delavirdine is a non-nucleoside reverse transcriptase inhibitor with potent in vitro activity against HIV-1 and is currently approved by the Food and Drug Administration as a component of combination therapy with appropriate antiretroviral agents for the treatment of HIV-1 infection.32

Shelton et al.21 showed in a small case-series of five HIV-positive patients with hypochlorhydria (intragastric pH >3) and positive H. pylori serology that eradication treatment reversed hypochlorhydria and concomitantly led to a significant increase in delavirdine absorption. The same authors22 showed in a randomized crossover study conducted on 21 HIV-positive with (= 11) and without (= 10) hypochlorhydria that the absorption of delavirdine is reduced by 47% in hypochlorhydric patients and may be improved by the concomitant administration of delavirdine with orange juice (57% increase) suggesting that in HIV-infected subjects, the absorption of delavirdine may be improved by an acidic gastric pH. A positive H. pylori serology was reported in 62% of the investigated patients, but eradication treatment was not performed in this study. Hypochlorhydria has been reported frequently among HIV-infected subjects33–35 and the presence of H. pylori infection has been reported to be the most significant predictor for increased intragastric pH in HIV-positive patients.36 Despite the limits of reduced sample size and the not-controlled study design, taken together, these papers suggest in HIV-positive subjects a causative role of hypochlorhydria in impaired delavirdine absorption, in whom reduced acid secretion is often related to the presence of H. pylori infection. Indeed, delavirdine is a weak basic compound, which is many times less soluble at non-acidic pH, making the influence of gastric pH on the absorption of delavirdine biochemically plausible.37

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Helicobacter pylori infection is still highly prevalent and is associated with divergent outcomes that range from asymptomatic gastritis to more serious conditions such as peptic ulcer disease and gastric neoplasia.38 As a consequence of chronic inflammatory response to H. pylori infection, some of the physiological functions of the stomach may be altered, in particular, gastric acid secretion.9 The effect of H. pylori infection on gastric acid secretion depends on severity and distribution of gastritis: an inflammatory response involving the acid secreting corpus region may lead to hypochlorhydria.10 Drug absorption is one of the critical determinants influencing the efficacy of orally administered therapy and, in turn, some gastric functions such as gastric secretion and motility may affect drug absorption.1, 2 Thus, it is reasonable that H. pylori-induced gastritis may affect the absorption of orally administered drugs.

The present systematic review identified five papers,18–22 which addressed the item of impaired drug absorption associated with H. pylori-infection, suggesting that this question has raised little attention so far. The identified papers investigated the impaired absorption of three drugs, l-dopa,18, 19 thyroxine20 and delavirdine,21, 22 which are widely used for the treatment of frequent conditions, such as Parkinson’s disease, thyroid disorders and HIV-positivity respectively.

Interestingly, it has been reported that patients with thyroid disease, in particular of autoimmune origin, and patients with Parkinson’s disease have an increased prevalence of H. pylori infection, often with CagA positive strains, with ORs ranging from 2 to 3 compared to control subjects.26, 39–41 As regards HIV-positive subjects, the prevalence of H. pylori infection seems not to be different from that in HIV-negative subjects,36, 42 but it has been observed that the histological score of H. pylori-gastritis was more severe in HIV-positive subjects.43 Thus, the results of this review suggest that the impaired absorption of thyroxine, l-dopa and delavirdine associated with H. pylori infection may have potentially relevant clinical implications, because these drugs are often used in disorders in which the co-presence of H. pylori infection seems to be frequent and/or severe.

A further finding which emerged from the present review was that one of the likely pathophysiological mechanisms for impaired drug absorption associated with H. pylori infection seems to be reduced gastric acid secretion. Alterations in gastric acidity seem to play an important role in the drug absorption process, probably due to its influence on the degree of ionization as well as the pH-dependent solubility of several drugs.4 The gastrointestinal absorption of thyroxine, l-dopa and delavirdine has been reported to be pH-sensitive.20, 24, 37 Indeed, the concomitant treatment with omeprazole was associated with an increased need for thyroxine, which was reversed to the previous need of the drug when omeprazole therapy was discontinued20 and thyroid disorders have been described to be frequently associated with atrophic body gastritis and hypochlorhydria.31, 44 The absorption parameters of delavirdine improved in hypochlorhydric subjects by the concomitant administration of an acidic beverage22 and the presence of hypochlorhydria has been reported frequently among HIV-infected subjects,33–35 for which H. pylori infection has been indicated as the most significant predictor.36 In the studies regarding the impaired absorption of l-dopa,18, 19 gastric acidity was not assessed, but Parkinson’s disease affects elderly patients more frequently23, 26 and the prevalence of chronic atrophic gastritis and hypochlorhydria strongly increases with age and long-standing H. pylori infection.45, 46

Helicobacter pylori gastritis involving the corporal mucosa may lead to hypochlorhydria by inhibiting the acid secreting cells due to the inflammatory response, in particular due to interleukin-1ß and, in this case, there is no loss of parietal cell mass and hypochlorhydria may be reversible after cure of H. pylori infection; hypochlorhydria may be also the result of loss of oxyntic mucosa due to atrophy as a consequence of long-standing H. pylori infection and in this case, the reversal of impaired acid secretion after cure of infection is still a matter of debate.10, 13, 25 In this review, in four of the selected studies, eradication treatment led to an improvement of drug absorption suggesting that eventual recovery of gastric acid secretion after cure of infection may be the basis for normalization of absorption of the drug. Indeed, there is evidence in vitro and in vivo that eradication treatment may reverse reduced acid secretion.25, 47, 48 Taking into account that impaired absorption of orally administered drugs may lead to an increase in the dosage to maintain or achieve efficacy of the medical therapy and thus increase costs of medical treatment, assessment of H. pylori-gastritis involving the corporal mucosa and possible subsequent eradication treatment may be a useful strategy to optimize orally administered therapy in these patients.

In the general practice, when prescribing a therapy indicated for a specific medical problem, physicians are often not aware of or pay little attention to the eventually impaired pharmacokinetics of some drugs in relationship to an alteration in the gastric mucosa and/or gastric acid secretion. Thus, among reasons for failure of orally administered therapy, whose absorption is potentially affected by intragastric pH, the eventual presence of H. pylori-related gastritis and/or associated hypochlorhydria should be considered, a condition which may be reversed by eradication treatment of H. pylori.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We thank Ms Felicia Proietti and her collaborators, University Library, 2nd Medical School, University La Sapienza, Rome, for their support in the search of hard copies of the reviewed papers. Declaration of personal interests: None. Declaration of funding interests: This work was supported by grants from the Italian Ministry for University and Research 2005 and University Sapienza Rome 2006.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References