Use of the erythromycin breath test for in vivo assessments of cytochrome P4503A activity and dosage individualization

Cepeda, M. Soledad; Farrar, J; Roa, Jairo H.; Boston, Raymond C.; Meng, Qingzhen; RUIZ, F; Carr, D.B.; STROM, B

doi:10.1016/s0009-9236(01)45600-1

Cited by 86 publications

(36 citation statements)

References 31 publications

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“…However, it is possible that the contribution of UGT2B7 to these activities (and isoform selectivity of the activities) might be enhanced at lower morphine concentrations (less than 500 M), since the apparent K m of UGT2B7 is low relative to the K m of HLMs. Indeed, plasma morphine concentrations in patients following a standard clinical dose of this drug rarely exceed 300 ng/ml, or about 1 M (Cepeda et al, 2001). Unfortunately, methodological limitations in the sensitivity of the current morphine glucuronidation assay precluded such an analysis in this study.…”

Section: Court Et Almentioning

confidence: 97%

EVALUATION OF 3′-AZIDO-3′-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7^*2 POLYMORPHISM

Court¹,

Krishnaswamy²,

Qin³

et al. 2003

Drug Metab Dispos

232

192

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ABSTRACT:UDP-glucuronosyltransferase 2B7 (UGT2B7) is involved in the glucuronidation of a wide array of clinically important drugs and endogenous compounds in humans. The aim of this study was to identify an isoform-selective probe substrate that could be used to investigate genetic and environmental influences on glucuronidation mediated by UGT2B7. Three potential probe substrates [3-azido-3-deoxythymidine (AZT), morphine, and codeine], were evaluated using recombinant UGTs and human liver microsomes (HLMs; n ‫؍‬ 54). Of 11 different UGTs screened, UGT2B7 was the principal isoform mediating AZT glucuronidation, morphine-3-glucuronidation, and morphine-6-glucuronidation. Codeine was glucuronidated equally well by UGT2B4 and UGT2B7. Enzyme kinetic analysis of these activities typically showed higher apparent K m values for HLMs (pooled and individual) compared with UGT2B7.This difference was least (less than 2-fold higher K m ) for AZT glucuronidation and greatest (3-to 6-fold higher K m ) for codeine glucuronidation. Microsomal UGT2B7 protein content correlated well with AZT glucuronidation (r s ‫؍‬ 0.77), to a lesser extent with morphine-3-glucuronidation (r s ‫؍‬ 0.50) and morphine-6-glucuronidation (r s ‫؍‬ 0.51), but very weakly with codeine glucuronidation (r s ‫؍‬ 0.33). Livers were also genotyped for the UGT2B7*2 (H268Y) polymorphism. No effect of genotype on microsomal glucuronidation or UGT2B7 protein content was observed. In conclusion, although both AZT and morphine can serve as in vitro probe substrates for UGT2B7, AZT appears to be more selective than morphine. Codeine is not a useful UGT2B7 probe substrate because of significant glucuronidation by UGT2B4. The UGT2B7*2 polymorphism is not a determinant of glucuronidation of AZT, morphine, or codeine in HLMs.

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Section: Court Et Almentioning

confidence: 97%

EVALUATION OF 3′-AZIDO-3′-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7^*2 POLYMORPHISM

Court¹,

Krishnaswamy²,

Qin³

et al. 2003

Drug Metab Dispos

232

192

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“…It is described that between one fifth and one third of patients experience nausea when using opioids (10,11). Nausea and vomiting is also very unfortunate because of the risk for aspiration, if there is a need for treatment with continuous positive pressure (CPAP).…”

Section: Why Morphine In Ahf May Cause Harmmentioning

confidence: 99%

Morphine in acute heart failure

Agewall

2017

J. Thorac. Dis.

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“…In addition to the interindividual variability, ethnic differences in morphine pharmacokinetics and pharmacodynamics were reported (Cepeda et al, 2001). Recent clinical studies indicate that the large interindividual and inter-racial variability in drug responses occurs as a result of molecular alterations at the level of drug-metabolizing enzymes, drug targets/receptors, and drug transport proteins.…”

mentioning

confidence: 99%

Sequence Variability and Candidate Gene Analysis in Two Cancer Patients with Complex Clinical Outcomes During Morphine Therapy

Hirota¹,

Ieiri²,

Takane³

et al. 2003

Drug Metabolism and Disposition

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:In this case report, we present genetic differences in two morphine-related gene sequences, UDP-glucuronosyltransferase 2B7 (UGT2B7) and opioid receptors (MOR1), in two cancer patients whose clinical responses to morphine were very different [i.e., sensitive (patient 1) and low responder (patient 2)]. In addition, allelic variants in the UGT2B7 gene were analyzed in 46 Japanese individuals. Amplified DNA fragments for the two genes of interest were screened using single strand conformation polymorphism and then sequenced. In the UGT2B7 gene, 12 single nucleotide polymorphisms (SNPs) were newly identified with an allelic frequency ranging from 0.022 to 0.978. Six SNPs in the promoter region (A-1302G, T-1295C, T-1111C, G-899A, A-327G, and T-125C) and two coding SNPs (UGT2B7*2 in exon 2 and C1059G in exon 4) appeared to be consistently linked. Remarkable differences in the nucleotide sequence of UGT2B7 were observed between the two patients; in contrast to patient 1 who had "reference" alleles at almost SNP positions, but a rare ATTGAT*2(AT)C haplotype as homozygosity, patient 2 was a homozygous carrier for the predominant GCCAGC*1(TC)G sequence. Serum morphine and two glucuronide concentrations in patient 2 suggest that the predominant GCCAGC*1G sequence was not associated with a "poor metabolizer" phenotype. In the MOR1 gene, patient 1 had no SNPs, whereas patient 2 was a heterozygous carrier for both the G-1784A and A118G alleles. The present study describes substantial differences in genotype patterns of two genes of interest between the two patients. The results necessitate larger trials to confirm these observations in larger case control studies.

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Use of the erythromycin breath test for in vivo assessments of cytochrome P4503A activity and dosage individualization

Abstract: Ethnicity influences the response to morphine. Native Indians are more susceptible to morphine depression of the ventilatory response than Caucasians, despite the higher serum M6G levels in Caucasians.

Cited by 86 publications

References 31 publications

EVALUATION OF 3′-AZIDO-3′-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7^*2 POLYMORPHISM

EVALUATION OF 3′-AZIDO-3′-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7^*2 POLYMORPHISM

Morphine in acute heart failure

Sequence Variability and Candidate Gene Analysis in Two Cancer Patients with Complex Clinical Outcomes During Morphine Therapy

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Use of the erythromycin breath test for in vivo assessments of cytochrome P4503A activity and dosage individualization

Abstract: Ethnicity influences the response to morphine. Native Indians are more susceptible to morphine depression of the ventilatory response than Caucasians, despite the higher serum M6G levels in Caucasians.

Cited by 86 publications

References 31 publications

EVALUATION OF 3′-AZIDO-3′-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7*2 POLYMORPHISM

EVALUATION OF 3′-AZIDO-3′-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7*2 POLYMORPHISM

Morphine in acute heart failure

Sequence Variability and Candidate Gene Analysis in Two Cancer Patients with Complex Clinical Outcomes During Morphine Therapy

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EVALUATION OF 3′-AZIDO-3′-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7^*2 POLYMORPHISM

EVALUATION OF 3′-AZIDO-3′-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7^*2 POLYMORPHISM