Interaction of Buprenorphine and Its Metabolite Norbuprenorphine With Cytochromes P450 in Vitro

Zhang, Wenjiang; Ramamoorthy, Yamini; Tyndale, Rachel F.; Sellers, Edward M.

doi:10.1124/dmd.31.6.768

Cited by 57 publications

(44 citation statements)

References 30 publications

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“…Other minor pathways involving, for example, CYP2C8 and CYP2D6, have also been reported (Zhang et al, 2003;Picard et al, 2005). In this study, metabolism via glucuronidation is not captured because the study was focused only on five major P450s, and UDP-glucuronosyltransferase cofactor was not used.…”

Section: Discussionmentioning

confidence: 99%

Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. II. In Vitro-in Vivo Correlation with Ketoconazole

Lu¹,

Hatsis²,

Berg³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Traditional cytochrome P450 (P450) based drug-drug interaction (DDI) predictions are based on the ratio of an inhibitor's physiological concentration [I] and its inhibition constant K i . Determining [I] at the enzymatic site, although critical for predicting clinical DDIs, remains a technical challenge. In our previous study, a novel approach using cryopreserved human hepatocytes suspended in human plasma was investigated to mimic the in vivo concentration of ketoconazole at the enzymatic site (Lu et al., 2007), effectively eliminating the estimation of the elusive [I] value. P450 inhibition in this system appears to model that in vivo. Using the ketoconazole inhibition information in a human hepatocyte-plasma suspension together with quantitative P450 phenotypic information, we successfully predicted the pharmacokinetic DDIs for a small set of drugs, such as theophylline, tolbutamide, omeprazole, desipramine, midazolam, loratadine, cyclosporine, and alprazolam, as well as an investigational compound. For the applicability of this model on a wider scale the in vitro-in vivo correlation data set needed to be expanded. However, for most drugs in the literature there is not enough quantitative information on the involvement of individual P450s to predict DDIs retrospectively. To facilitate that, in this study we determined quantitative P450 phenotyping for seven marketed drugs: budesonide, buprenorphine, loratadine, sirolimus, tacrolimus, docetaxel, and methylprednisolone. Augmentation of the new data set with the one generated previously produced broader a database that provided further support for the wider applicability of this approach using ketoconazole as a potent CYP3A inhibitor. This application is predicted to be equally effective with other P450 inhibitors that are not substrates of efflux pumps.The prediction of pharmacokinetic drug-drug interactions (DDIs) for humans in the recent past has relied heavily on the ratio [I]/K i , use of which has shown some success. However, to date its broader applicability has not been demonstrated, mainly because of the elusive parameter [I], which signifies the free inhibitor concentration at the enzyme site. Because the value cannot be determined directly, scientists have resorted to finding the next best parameter to estimate that concentration, as described in the previous communication (Lu et al., 2007). But the applicability of one method over another generally leads to not-so-useful predictions. Thus, use of the [I]/K i ratio to predict drug-drug interaction remains a challenge.We recently proposed a new method for DDI prediction that enabled us to avoid the dependence on [I]/K i ratio (Lu et al., 2007). In our method, various concentrations of the inhibitor ketoconazole were incubated in human hepatocytes that were suspended in human plasma to construct an inhibition titration curve. After equilibrium, the major P450 activities remaining were measured using prototypical substrates. It was assumed that if an extracellular (plasma) concentration of that...

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Section: Discussionmentioning

confidence: 99%

Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. II. In Vitro-in Vivo Correlation with Ketoconazole

Lu¹,

Hatsis²,

Berg³

et al. 2008

Drug Metab Dispos

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“…Buprenorphine metabolism follows simple nonsaturable Michaelis-Menten kinetics. Buprenorphine inhibits CYP3A4, and CYP2D6 and norbuprenorphine inhibits CYP2D6, but both are weak enzyme inhibitors, and at the therapeutic levels, neither one will precipitate a drug interaction [56][57][58]. Buprenorphine and norbuprenorphine are conjugated by UGT1A1, UGT1A3, and UGT2B7.…”

Section: Metabolismmentioning

confidence: 98%

“…Aromatase (CYP19), rather than CYP3A4 or conjugases, is responsible for converting buprenorphine to norbuprenorphine in the placenta [57]. Buprenorphine does cross the placenta, and neonatal withdrawal can occur in babies born to a woman on buprenorphine.…”

Section: Metabolismmentioning

confidence: 99%

Buprenorphine in cancer pain

Davis

2005

Support Care Cancer

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Buprenorphine is a broad spectrum, highly lipophilic, and long-acting partial mu opioid receptor agonist that is noncross tolerant to other opioids. Buprenorphine can be given by several routes. Metabolism is through CYP3A4 and CYP2C8 and by conjugases. Constipation and sexual dysfunction appear to be less with buprenorphine than with other opioids. The recent development of a polymer matrix patch delivery system for buprenorphine prevents "dose dumping" and facilitates pain management in those unable to take oral analgesics. Sublingual buprenorphine has been combined with naloxone to prevent illicit conversion to parenteral administration. Buprenorphine has been used extensively to control cancer pain. In certain clinical situations, buprenorphine may have particular advantages over other opioids.

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“…According to their reports, BN competitively inhibits BF 1Ј-hydroxylation (K i ϭ21 mM) and DM O-demethylation (K i ϭ10 mM) in HLM respectively (Table 1). 11,12) When we evaluated the inhibition by BN against CYP2D6 using the high throughput method in the present study, BN strongly inhibited it (IC 50 ϭ0.25 mM). Although the substrate concentration (1.5 mM) in this assay was near to the reported K m value (1.0 mM) for this reaction, 4) this IC 50 value showed a large discrepancy with the above reported K i values in HLM.…”

mentioning

confidence: 99%

“…10,12) Consequently, in inhibition studies with BN, its concentration could decrease in HLM containing CYP3A4, but not in rCYP2D6 microsomes. We also considered elimination rate of the inhibitor to be a probable cause of the discrepancy in inhibitory potency between the two systems.…”

mentioning

confidence: 99%

Effect of Nonspecific Binding to Microsomes and Metabolic Elimination of Buprenorphine on the Inhibition of Cytochrome P4502D6

Umeda

Harakawa

Yamamoto

et al. 2005

Biological & Pharmaceutical Bulletin

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The inhibition of drug-metabolizing enzymes, such as cytochrome P450 (CYP) often can lead to alterations in the extent of exposure to coadministered drug. Such drug interactions can limit the use of a drug because of adverse clinical effects, depending upon the potential for the toxicity of affected drug. Since CYP2D6 is one of the important human CYP isozymes and metabolizes more than 20% of commercially available drugs, 1) a profound understanding of the inhibitory potency against CYP2D6 of the drug candidates is important in the discovery and development of new drugs. The pharmaceutical industry routinely has assessed the risk of the drug interaction by determining the inhibitory effect of the candidates on the rate of a probe reaction that represents of a specific CYP enzyme activity in human liver microsomes (HLM).2,3) The in vitro findings obtained with one probe substrate are usually extrapolated to the potential of compound to affect all substrates of the same enzyme. Bufuralol (BF) 1Ј-hydroxylation and dextromethorphan (DM) O-demethylation have generally been used as probe reactions for the evaluation of CYP2D6 inhibition. Buprenorphine (BN) is a semi-synthetic, highly lipophilic opioid derivative of the morphine alkaloid tebaine and is often prescribed for the treatment of moderate to severe pain in cases of postoperative and terminal cancer. 7) BN is metabolized by N-dealkylation of its cyclopropyl methyl group to norbuprenorphine (NBN). 8) N-Dealkylation of BN in HLM is mainly catalyzed by CYP3A4. 9,10) Uehara et al. and Zhang et al. reported that BN competitively inhibits not only CYP3A4 but also CYP2D6. According to their reports, BN competitively inhibits BF 1Ј-hydroxylation (K i ϭ21 mM) and DM O-demethylation (K i ϭ10 mM) in HLM respectively (Table 1). 11,12)When we evaluated the inhibition by BN against CYP2D6 using the high throughput method in the present study, BN strongly inhibited it (IC 50 ϭ0.25 mM). Although the substrate concentration (1.5 mM) in this assay was near to the reported K m value (1.0 mM) for this reaction, 4) this IC 50 value showed a large discrepancy with the above reported K i values in HLM.Margolis et al. reported that the inhibitory potency of some highly lipophilic drugs against CYP2D6 decreased with an increase in microsomal concentration. This is caused by the decrease of free concentrations of inhibitors due to an increase in the nonspecific binding to microsomes.13) As BN shows high lipophilicity, it could have high binding affinity to microsomes. Thus, we considered nonspecific binding to be a probable cause of the discrepancy.On the other hand, BN is rapidly metabolized by CYP3A4, but not by CYP2D6 at low substrate concentrations. Recently, the pharmaceutical industry has employed the high-throughput method for the evaluation of cytochrome P450 (CYP) inhibition, using a combination of the heterologously expressed enzyme and a fluoregenic substrate. When buprenorphine (BN), a potent mixed agonist-antagonist analgesic, was evaluated by this method, it exhibited pot...

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Interaction of Buprenorphine and Its Metabolite Norbuprenorphine With Cytochromes P450 in Vitro

Cited by 57 publications

References 30 publications

Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. II. In Vitro-in Vivo Correlation with Ketoconazole

Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. II. In Vitro-in Vivo Correlation with Ketoconazole

Buprenorphine in cancer pain

Effect of Nonspecific Binding to Microsomes and Metabolic Elimination of Buprenorphine on the Inhibition of Cytochrome P4502D6

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