Methadone binding to orosomucoid (α1-acid glycoprotein): Determinant of free fraction in plasma

Romach, Myroslava K.; Piafsky, Kenneth M.; Abel, James G.; Khouw, V; Sellers, Edward M.

doi:10.1038/clpt.1981.34

Cited by 101 publications

(38 citation statements)

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“…In the current study, a negative relationship was observed between AGP concentrations and the unbound (active) percentage of R-methadone, similar to previously reported findings (20). As shown by the parallel decreasing slopes of the linear regression lines in Fig.…”

Section: Discussionsupporting

confidence: 78%

Pharmacokinetic Interaction between Telaprevir and Methadone

Heeswijk

Verboven

Vandevoorde

et al. 2013

Antimicrob Agents Chemother

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dHepatitis C virus (HCV) antibody is present in most patients enrolled in methadone maintenance programs. Therefore, interactions between the HCV protease inhibitor telaprevir and methadone were investigated. The pharmacokinetics of R-and S-methadone were measured after administration of methadone alone and after 7 days of telaprevir (750 mg every 8 h [q8h]) coadministration in HCV-negative subjects on stable, individualized methadone therapy. Unbound R-methadone was measured in predose plasma samples before and during telaprevir coadministration. Safety and symptoms of opioid withdrawal were evaluated throughout the study. In total, 18 subjects were enrolled; 2 discontinued prior to receiving telaprevir. The minimum plasma concentration in the dosing interval (C min ), the maximum plasma concentration (C max ), and the area under the plasma concentration-time curve from h 0 (time of administration) to 24 h postdose (AUC 0 -24 ) for R-methadone were reduced by 31%, 29%, and 29%, respectively, in the presence of telaprevir. The AUC 0 -24 ratio of S-methadone/R-methadone was not altered. The median unbound percentage of R-methadone increased by 26% in the presence of telaprevir. The R-methadone median (absolute) unbound C min values in the absence (10.63 ng/ml) and presence (10.45 ng/ml) of telaprevir were similar. There were no symptoms of opioid withdrawal and no discontinuations due to adverse events. In summary, exposure to total R-methadone was reduced by approximately 30% in the presence of telaprevir, while the exposure to unbound R-methadone was unchanged. No symptoms of opioid withdrawal were observed. These results suggest that dose adjustment of methadone is not required when initiating telaprevir treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT00933283.) H epatitis C virus (HCV) infection is widespread among previous intravenous drug users who share syringes and drug preparation equipment (1). Methadone is commonly used as a maintenance therapy for opiate dependence, and a prevalence of HCV antibody of up to 96% has been reported among patients enrolled in methadone maintenance programs (2). Telaprevir is a novel agent for the treatment of genotype 1 chronic HCV infection in adults, as shown by significantly improved rates of sustained HCV RNA clearance in combination therapy with pegylated interferon/ribavirin compared with pegylated interferon/ ribavirin alone (3-5). Use of telaprevir for treatment of HCV infection includes patients receiving methadone maintenance therapy.Methadone is a synthetic narcotic analgesic that is administered as a combination of R-and S-isomers, with the R-isomer being mainly responsible for the opioid effect (6, 7), whereas the S-isomer has been linked to prolongation of the corrected QT (QTc) (where QT represents the time between the start of the Q wave and the end of the T wave) (8). Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP). Cytochro...

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Section: Discussionsupporting

confidence: 78%

Pharmacokinetic Interaction between Telaprevir and Methadone

Heeswijk

Verboven

Vandevoorde

et al. 2013

Antimicrob Agents Chemother

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“…Aprindine (Teirlynck et al, 1982) Bupivacaine (Denson et al, 1984) Disopyramide (Lima et al, 1981) Lignocaine (Routledge et al, 1980a) Pirmenol (Hammill et al, 1982) Quinidine (Nilsen et al, 1978) Verapamil (McGowan et al, 1983) Opiates Methadone (Romach et al, 1981) Pethidine (Nation, 1981) Antidepressants Amitriptyline (Pike & Skuterud, 1982) Imipramine Nortriptyline (Pike & Skuterud, 1982) Variability in protein binding…”

Section: Antiarrhythmicsmentioning

confidence: 99%

The plasma protein binding of basic drugs.

Routledge¹

1986

Brit J Clinical Pharma

168

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The plasma protein binding of basic drugs appears to vary more than was at first assumed and is related to the marked intra‐and interindividual differences in one of the chief binding proteins, AAG. Changes in AAG concentrations will result in alterations in the distribution and metabolism of basic drugs which will complicate the interpretation of the relationship between total drug concentration and drug efficacy or toxicity. For some drugs, e.g. lignocaine, direct measurement of free concentrations may improve their clinical use but rapid and reliable techniques are as yet not readily available.

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“…The pharmacologic effect of these agents is proportional to the plasma total drug concentration (3,4). The clinical interpretation of plasma drug levels is complicated by the fact that many basic lipophilic drugs are bound by a plasma globulin, orosomucoid, i.e., a,-acid glycoprotein (5)(6)(7). Orosomucoid is an acute-phase reactant and serum levels of this protein rise severalfold in a variety of inflammatory illnesses (8).…”

Section: Introductionmentioning

confidence: 99%

Transport of Propranolol and Lidocaine through the Rat Blood-Brain Barrier. PRIMARY ROLE OF GLOBULIN-BOUND DRUG

Pardridge¹,

Sakiyama²,

Fierer³

1983

J. Clin. Invest.

112

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A B S T R A C T Basic lipophilic drugs such as propranolol and lidocaine are strongly bound by a1-acid glycoprotein, also called orosomucoid. Although the liver is known to rapidly clear plasma protein-bound propranolol or lidocaine, it is generally regarded that peripheral tissues, such as brain or heart, are only exposed to the small fraction of drug that is free or dialyzable in vitro. The "free drug" hypothesis is subjected to direct empiric testing in the present studies using human sera and an in vivo rat brain paradigm.Serum from 27 human subjects (normal individuals, newborns, or patients with either metastatic cancer or rheumatoid arthritis) were found to have up to a sevenfold variation in orosomucoid concentrations. The free propranolol or lidocaine as determined in vitro by equilibrium dialysis at 370C varied inversely with the orosomucoid concentration. Similarly the rate of transport of propranolol or lidocaine through the blood-brain barrier (BBB) was inversely related to the existing serum concentration of orosomucoid. However, the inhibition of rat brain extraction of drug by orosomucoid in vivo was only about one-fifth of that predicted by free drug measurements in vitro. This large discrepancy suggested orosomucoid-bound drug was readily available for transport into brain in vivo.Studies using purified human orosomucoid in the rat brain extraction assay also showed that orosomucoidbound propranolol or lidocaine is readily transported through the BBB. Conversely, albumin-bound propranolol or lidocaine was not transported through the BBB. The studies using albumin provide evidence that

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Methadone binding to orosomucoid (α1-acid glycoprotein): Determinant of free fraction in plasma

Cited by 101 publications

References 1 publication

Pharmacokinetic Interaction between Telaprevir and Methadone

Pharmacokinetic Interaction between Telaprevir and Methadone

The plasma protein binding of basic drugs.

Transport of Propranolol and Lidocaine through the Rat Blood-Brain Barrier. PRIMARY ROLE OF GLOBULIN-BOUND DRUG

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