Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys

Lelas, Snjezana; Wegert, Sandra; Otton, S V; Sellers, Edward M.; France, Charles P.

doi:10.1016/s0376-8716(98)00169-0

Cited by 21 publications

(11 citation statements)

References 15 publications

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“…A similar conclusion was drawn from studies on psychomotor effects and subject self-reporting of drug experience following oxycodone administration (Heiskanen et al, 1998). Studies examining O-demethylation of hydrocodone to hydromorphone have also shown that the parent compound appears to be responsible for analgesic effects in rats (Tomkins et al, 1997), monkeys (Lelas et al, 1999), and humans (Otton et al, 1993).…”

mentioning

confidence: 68%

Activation of G-Proteins by Morphine and Codeine Congeners: Insights to the Relevance of O- and N-Demethylated Metabolites at μ- and δ-Opioid Receptors

Thompson¹,

Wojno²,

Greiner³

et al. 2003

J Pharmacol Exp Ther

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Phenotypic differences in analgesic sensitivity to codeine (3-methoxymorphine) results from polymorphisms in cytochrome P450 -2D6, which catalyzes O-demethylation of codeine to morphine. However, O-demethylation reportedly is not required for analgesic activity of the 7,8-saturated codeine congeners dihydrocodeine, hydrocodone, and oxycodone. This study determined the potency and efficacy of these compounds and their demethylated derivatives to stimulate -and ␦-opioid receptor-mediated G-protein activation using agonist-stimulated guanosine 5Ј-O-(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) binding. Results showed that 7,8-saturated codeine congeners were more efficacious than codeine in activating -receptors, but only dihydrocodeine was more efficacious at ␦-receptors. Hydrocodone and oxycodone were ϳ10-fold more potent than codeine and dihydrocodeine at either receptor. Morphine-like compounds with a 3-hydroxy group were ϳ30-to 100-fold more potent than their 3-methoxy analogs at the -receptor, and these compounds generally exhibited greater efficacy (e.g., morphine produced 2-fold greater maximal stimulation than codeine). Removal of the N-methyl group did not affect efficacy or potency of codeine congeners to activate -receptors, whereas this modification generally increased efficacy but decreased potency of morphine congeners. At the ␦ receptor, morphine congeners showed greater potency and structuredependent differences in efficacy compared with codeine congeners, whereas removal of the N-methyl group had effects similar to those observed at the -receptor. These results demonstrate that 7,8-saturated codeine congeners are more efficacious than codeine, which may explain their lack of requirement for 3-O-demethylation in vivo. Nonetheless, because all 7,8-saturated codeine congeners were significantly less potent than their morphine derivatives, further research is needed to understand the relationship between metabolism and in vivo activity of these compounds.The opioid analgesic, codeine (3-methoxymorphine), undergoes several metabolic routes including N-and O-demethylation, as well as glucuronidation (Dayer et al., 1988;Mikus et al., 1991;Caraco et al., 1996;Yu et al., 2002). It is well established that codeine must be O-demethylated to morphine to produce analgesia in both humans (Chen et al., 1991) and rats (Mikus et al., 1991;Cleary et al., 1994). In humans, cytochrome P450 -2D6 (CYP-2D6) catalyzes this reaction, and individuals with dysfunctional allelic variants of this gene are phenotypically described as poor metabolizers (PMs) and are less sensitive to codeine. Individuals expressing multiple copies of active CYP-2D6 are extensive metabolizers (EMs) and are more sensitive to codeine. EMs can exhibit the PM phenotype, however, when codeine is coadministered along with a CYP-2D6 inhibitor such as quinidine. The requirement for O-demethylation is not surprising given that the reported K i values for binding to -opioid receptors is 200 times higher for codeine than for morphine (Chen et al., 1991...

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confidence: 68%

Activation of G-Proteins by Morphine and Codeine Congeners: Insights to the Relevance of O- and N-Demethylated Metabolites at μ- and δ-Opioid Receptors

Thompson¹,

Wojno²,

Greiner³

et al. 2003

J Pharmacol Exp Ther

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“…Abuse liability testing of hydrocodone has been conducted in non-humans, and in opioid-abusing, and a selected sub-population of non-opioid-abusing, human volunteers. Hydrocodone functions as a reinforcer in rats, and in drug discrimination studies substitutes for morphine in both rats and primates (Tomkins et al 1997;Lelas et al 1999). The abuse liability of hydrocodone (SC, IM, IV) has been examined in two studies in people with a history of abusing opioids but who were not currently physically dependent, i.e.…”

Section: Introductionmentioning

confidence: 98%

Characterizing the subjective, psychomotor, and physiological effects of a hydrocodone combination product (Hycodan) in non-drug-abusing volunteers

Zacny

2003

Psychopharmacology

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“…Production of the active metabolites of hydrocodone (hydromorphone) and oxycodone (oxymorphone) is reduced in CYP2D6 PMs (Otton et al, 1993;Heiskanen et al, 1998). However, there is little evidence of a difference in effect between EMs and PMs in human studies (Otton et al, 1993;Kaplan et al, 1997;Heiskanen et al, 1998) or in animal models (Tomkins et al, 1997;Lelas et al, 1999).…”

Section: Antipsychoticsmentioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys

Cited by 21 publications

References 15 publications

Activation of G-Proteins by Morphine and Codeine Congeners: Insights to the Relevance of O- and N-Demethylated Metabolites at μ- and δ-Opioid Receptors

Activation of G-Proteins by Morphine and Codeine Congeners: Insights to the Relevance of O- and N-Demethylated Metabolites at μ- and δ-Opioid Receptors

Characterizing the subjective, psychomotor, and physiological effects of a hydrocodone combination product (Hycodan) in non-drug-abusing volunteers

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

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