THE EFFECT OF CHANGES IN GASTRIC pH INDUCED BY OMEPRAZOLE ON THE ABSORPTION AND RESPIRATORY DEPRESSION OF METHADONE

Castro, J. De; Aguirre, C; Rodríguez-Sasiaín, J M; Tamayo, Eduardo; Garrido, María J.; Calvo, Rosario

doi:10.1002/(sici)1099-081x(199610)17:7<551::aid-bdd967>3.0.co;2-1

Cited by 20 publications

(11 citation statements)

References 3 publications

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“…It was suggested that omeprazole interfered with the H + /K + ATPase proton pump that irreversibly modifies gastric pH. A change in the gastric microenvironment altered the absorption capabilities, and led to increased plasma levels of methadone 132 . A study by Foster et al 22 examined omeprazole's interaction with hepatic CYP P450.…”

Section: Omeprazolementioning

confidence: 99%

Methadone: a review of drug-drug and pathophysiological interactions

Kapur

Hutson²,

Chibber

et al. 2011

Critical Reviews in Clinical Laboratory Sciences

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Numerous established and potential drug interactions with methadone are clinically important in people treated with methadone either for addiction or for chronic pain. Methadone users often have comorbidities and are prescribed drugs that may interact with methadone. Methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6. Eighty-six percent of methadone is protein bound, predominately to α1-acid glycoprotein (AGP). Polymorphisms in or interactions with CYPs that metabolize methadone, changes in protein binding, and other pathophysiological conditions affect the pharmacokinetic properties of methadone. It is critical for health care providers who treat patients on methadone to have adequate information on the interactions of methadone with other drugs of abuse and other medications. We set out to describe drug-drug interactions as well as physiological and pathophysiological factors that may impact the pharmacokinetics of methadone. Using MEDLINE, we conducted a systematic search for papers and related abstracts published between 1966 and June 2010. Keywords that included methadone, drug-drug interactions, CYP P450 and AGP identified a total of 7709 papers. Other databases, including the Cochrane Database of Systematic Reviews and Scopus, were also searched; an additional 929 papers were found. Final selection of 286 publications was based on the relevance of each paper to the topic. Over 50 such interactions were found. Interactions of methadone with other drugs can lead to increased or decreased methadone drug levels in patients and result in potential overdose or withdrawal, respectively. The former can contribute to methadone's fatality. Prescribers of methadone and pharmacists should enquire about any new medications (including natural products and over-the-counter medications) periodically, and especially when an otherwise stable patient suddenly experiences drug craving, withdrawal or intoxication.

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Section: Omeprazolementioning

confidence: 99%

Methadone: a review of drug-drug and pathophysiological interactions

Kapur

Hutson²,

Chibber

et al. 2011

Critical Reviews in Clinical Laboratory Sciences

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“…6 Oral absorption is influenced by several factors including physicochemical properties of the drug, gastric motility, gut perfusion, and pH. 7 The average reported oral bioavailability of methadone is 70-80%, but published reports indicate that this may range widely from 36 to 100%. 6 This variability may be partly explained by the significant inter-individual variability in cytochrome P450 3A4 activity, which is responsible for metabolism of methadone.…”

Section: Absorptionmentioning

confidence: 99%

Pharmacokinetics of Methadone

Lugo

Satterfield

Kern

2005

J. Of Pain & Palliative Care Pharmacotherapy

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Methadone is a synthetic opioid that is effective for the relief of moderate-to-severe pain and for the treatment of opioid dependence. The pharmacokinetics of methadone differ from those of morphine in that methadone has a higher bioavailability, a much longer half-life, and is hepatically metabolized by cytochrome P450 enzymes. The pharmacokinetics of methadone are variable and an understanding of the factors that impact the onset, magnitude, and duration of analgesia is required to optimize therapy. Drug interactions are common and patients receiving methadone should be monitored closely for toxicity or therapeutic failure. Special populations in whom a change from the usual dosage regimen may be necessary include pediatric patients, patients with renal failure, the elderly, and pregnant women. To achieve an optimal dosage regimen, the clinician must have an understanding of the pharmacokinetics and pharmacodynamics of methadone in addition to the relationship between these variables and their patients' demographic and pathophysiologic characteristics. AMEDLINE search was performed to identify literature published between 1966 and May 2005 relevant to the pharmacokinetics of methadone. These publications were reviewed and the literature summarized regarding unique and clinically important elements of methadone disposition including its absorption profile, distribution, and metabolism/excretion. General dosing guidelines, dosage conversions from other opioids and pharmacokinetic issues in special populations are discussed.

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“…The potential of omeprazole to interfere with the oral bioavailability of aspirin,18 methadone,13 trovafloxacin,19 digoxin,20 theophylline,21 and nifedipine22 has been well documented in animals and humans. In most of these cases, the changes in bioavailability were attributed to changes in absorption related to an increase in intragastric pH.…”

Section: Discussionmentioning

confidence: 99%

“…Rats ( n = 104) received 3 mg/kg of RS ‐methadone (2 mg/mL in water) through the gastric intubator. This dose of RS‐ methadone was found to elicit analgesia with minor respiratory effects 13. Each animal received weight‐corrected volume (≈ 0.35 mL) of solution to individualize the dose.…”

Section: Methodsmentioning

confidence: 99%

“…Omeprazole irreversibly inhibits the H + /K + ‐ATPase proton pump so it modifies gastric pH and, consequently, it can also alter the absorption of drugs. It has been shown that after high oral doses of methadone (5 mg/kg) to the rat, intravenous (iv) omeprazole increases plasma levels of methadone and causes a respiratory depression 13. The aims of the present study were to further investigate the methadone–omeprazole interaction assessing simultaneously the kinetics and the dynamics of methadone [PK/pharmacodynamics (PD)] using analgesic doses in the rat.…”

Section: Introductionmentioning

confidence: 99%

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Effect of omeprazole on oral and intravenous RS‐methadone pharmacokinetics and pharmacodynamics in the rat

Carlos

Souich

Carlos

et al. 2002

Journal of Pharmaceutical Sciences

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The effect of omeprazole on oral and intravenous (iv) RS-methadone pharmacokinetics and pharmacodynamics was studied in awake, freely moving rats, which were divided in four groups: oral RS-methadone (3 mg/kg) was given (a) to a control group (CO oral ) (n ¼ 65) and (b) to an omeprazole pretreated group (OP oral ) (n ¼ 77), and iv RS-methadone (0.35 mg/kg) was administered (c) to a control group (CO iv ) (n ¼ 86) and (d) to an omeprazole pretreated group (OP iv ) (n ¼ 86). Omeprazole (2 mg/kg) was given iv 2 h before RS-methadone. Plasma concentrations of RSmethadone (Cp) were determined by high-performance liquid chromatography and analgesic response by tail flick for 0-180 min (oral) and 0-120 min (iv). RS-Methadone rate of absorption (mean AE SE) was faster in OP oral (k 01 ¼ 0.31 AE 0.04 min À1 ) than in CO oral (k 01 ¼ 0.05 AE 0.007 min À1 ), consequently plasma peak concentrations (C max ) were greater (197.41 AE 33.70 ng/mL versus 83.54 AE 7.97 ng/mL) and the time to reach C max (t max ) was shorter (11.23 AE 1.32 min versus 39.18 AE 1.74 min). Mean area under the Cptime curve (AUC 0-1 ) and hence bioavailability of oral RS-methadone were increased by omeprazole without significant changes in the elimination. Omeprazole did not affect the pharmacokinetics of iv RS-methadone. The changes of the analgesic effect of RSmethadone as a function of time were similar in all four groups. In the CO oral group, Cp and analgesic effect were defined by the E max model. The relationship between Cp and drug effect in the OP oral group showed a counterclockwise hysteresis (k e0 of 0.018 AE 0.006 min À1 ). For the iv groups (CO iv and OP iv ), the Cp-analgesic effect relationship was described by an E max sigmoid model and omeprazole did not affect the pharmacodynamic parameters. It is concluded that omeprazole causes an increase in the bioavailability of oral RS-methadone without modifying the analgesic response but affecting the Cp-effect relationship. ß

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THE EFFECT OF CHANGES IN GASTRIC pH INDUCED BY OMEPRAZOLE ON THE ABSORPTION AND RESPIRATORY DEPRESSION OF METHADONE

Cited by 20 publications

References 3 publications

Methadone: a review of drug-drug and pathophysiological interactions

Methadone: a review of drug-drug and pathophysiological interactions

Pharmacokinetics of Methadone

Effect of omeprazole on oral and intravenous RS‐methadone pharmacokinetics and pharmacodynamics in the rat

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