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Identification of Functionally Defective CYP4F11 Genetic Variants in Erythromycin Metabolism and 20-Hete Synthesis
Posters time above minimum inhibitory concentration (%T> MIC) of the recommended standard (normal renal function: 0.5 g every 8 h, moderate: 0.25 g every 8 h, severe renal impairment: 0.25 g every 12 h) and higher doses (normal: 1.0 g every 8 h, moderate: 0.5 g every 8 h, severe: 0.25 g every 8 h) against MICs of 0.5, 1 and 2 µg/mL exceeded 40% in all patients. When stratified by creatinine clearance, all the PK-PD breakpoints estimated by Monte Carlo simulation in three grades of renal function obtained in this study were higher than the previously reported PK-PD breakpoints for patients with urinary tract infection, an infection of lesser severity than ICU patients. Conclusions: These results suggest that the dosage regimen stratified by renal function derived from Japanese package insert may be sufficient to achieve effective treatment in ICU patients.
Identification of Functionally Defective CYP4F11 Genetic Variants in Erythromycin Metabolism and 20-Hete Synthesis M. Yi1; M.M. Parvez1; S.A. Cho1; D.H. Kim1; J.A. Jung2; S.J. Lee1; and J.-G. Shin1,2 1 Inje University College of Medicine, Busan, South Korea; and 2 Inje University Busan Paik Hospital, Busan, South Korea CYP4F11, together with CYP4F2, plays an important role in the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. We identified 21 variants by whole exome sequencing, including 4 non-synonymous variants in Korean subjects. The proteins of the wild-type CYP4F11 and the four coding variants (C276R, D315N, D374Y, and D446N) were expressed in Escherichia coli DH5α cells and purified with cytochrome P450-specific carbon monoxide difference spectra. Wild-type CYP4F2 was also expressed and purified to compare its activity with the CYP4F11 wild-type. Wildtype CYP4F11 exhibited the highest maximal clearance for erythromycin N-demethylase activity followed by the variants D374Y, D446N, C276R, and D315N. In particular, the CYP4F11 D315N protein showed about 50% decrease in intrinsic clearance compared to the wild type. The ability of wild-type CYP4F11 and the variants to synthesize 20-HETE from arachidonic acid was similar; the CYP4F11 D315N variant, however, showed only 68% of wild-type activity. Furthermore, the ability of CYP4F2 to synthesize 20-HETE was 1.7-fold greater than that of CYP4F11. Overall, our results suggest that the metabolism of CYP4F11 substrates may be reduced in individuals carrying the CYP4F11 D315N genetic variant, and individuals carrying the common D446N CYP4F11 variant likely exhibit comparable 20-HETE synthesis as individuals expressing wild-type CYP4F11.
New Drug Interaction: Clopidogrel Associated with Paclitaxel Induced Neuropathy in Cancer Patients T.K. Bergmann1,2; K. Agergaard3; M. Mau-Sørensen4; T.B. Stage5; T.L. Jørgensen1; R.E. Hassel6; K.D. Steffensen7; J.W. Pedersen8; M.L.H. Milo9; S.H. Poulsen4; A. Pottegård3; J. Hallas3; and K. Brosen3 1 Odense University Hospital, Odense, Denmark; 2Hospital of South West Denmark, Esbjerg, Denmark; 3University of Southern Denmark, Odense, Denmark; 4Copenhagen University Hospital, Copenhagen, Denmark; 5University of California, San Francisco, San Francisco, California; 6Aarhus University Hospital, Aarhus, Denmark; 7Lillebaelt Hospital, Vejle, Denmark; 8Copenhagen University Hospital, Herlev, Denmark; and 9Aalborg University Hospital, Aalborg, Denmark Background: The recent observation that clopidogrel acyl-β -D-glucuronide increases repaglinide area under the curve
August 2017
2-5 fold via CYP2C8 inhibition gave rise to the hypothesis that clinical relevant CYP2C8 mediated drug-drug-interaction occur between clopidogrel and paclitaxel. To test this hypothesis we performed a retrospective comparison of paclitaxel toxicity in patients treated with clopidogrel and low dose aspirin in breast cancer, ovarian cancer and other malignancies. Methods: The paclitaxel cohort was identified using databases from Danish hospitals and the National Database of Reimbursed Prescriptions. Patients with an active clopidogrel prescription were matched to patients with an active low dose aspirin prescription. Clinical oncologists reviewed patient records and recorded neuropathy and other toxicities. Tes tes tes. Results: The paclitaxel cohort included 7,730 patients of which 48 were exposed to clopidogrel and 85 patients exposed to low dose aspirin were included as controls. The overall hazard ratio of neuropathy associated with clopidogrel use by a cumulative dose of 1500 mg paclitaxel was 1.7 (95% CI, 0.9-3.0) compared to controls using low dose aspirin. This increased risk was accentuated in patients treated with high dose paclitaxel where the adjusted hazard ratio increased to 2.3 (95% CI, 1.1-4.5). Conclusions: Clopidogrel use is associated with an increased risk of paclitaxel induced eripheral sensory neuropathy.
The Influence of Drug Properties and Host Factors on Delayed Onset in Hepatotoxicity A. Gonzalez-Jimenez1; M. Chen2; K. McEuen2; J. Sanabria-Cabrera1; M. Slim1; C. Stephens1; A. Suzuki3; R.J. Andrade1; and M.I. Lucena1 1 IBIMA, H. Virgen de la Victoria, Universidad de Malaga, CIBERehd, Malaga, Spain; 2National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas; and 3University of Arkansas for Medical Sciences, Little Rock, Arkansas Background: Most drug-induced liver injury (DILI) patients develop symptoms while on drug treatments; however in some instances DILI develops after drug cessation. The reasons behind this delayed onset are currently unknown. In this study we aimed to determine drug-properties and host-factors potentially involved in DILI with delayed onset. Methods: 413 DILI cases from the Spanish DILI Registry were classified according to time of first symptom appearance, during (no delay onset, NDO) or after (delay onset, DO) causative agent treatment. The drugs were divided into two groups: drugs with (WP) or without potential (WOP) to induce delayed onset. Only oral drugs with at least three cases in the registry were selected. Amoxicillin-clavulanate (AC) cases were analyzed independently. Results: A total of 11 WP and 33 WOP drugs were found, corresponding to 204 and 209 cases, respectively. Ninety-four (46%) cases, of which 83% were due to AC, presented DO between 2-52 days after treatment cessation. The WP drug cases, omitting AC cases, showed shorter duration of treatment (11 vs 54 days, p= 0.0001), time to onset (14 vs 40 days, p= 0.0001) and higher mean dosage (744 vs 374 mg, p= 0.0001) than the cases induced by WOP drugs. The DO cases showed lower incidence of comorbidities (p= 0.0001). In terms of drug properties, the WP drugs showed lower ratio of hepatic metabolism (p= 0.0190) and higher proportion of parental drug excretion (p= 0.0015). The interactions analyzed showed that drugs with mitochondrial liability have stronger effect on delayed onset in younger patients, females and absence of cardiac diseases. Conclusions: Delayed onset potential appears associated with higher drug dose, shorter treatment and less comorbidities. The fact that
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Identification of Functionally Defective CYP4F11 Genetic Variants in Erythromycin Metabolism and 20-Hete Synthesis M. Yi1; M.M. Parvez1; S.A. Cho1; D.H. Kim1; J.A. Jung2; S.J. Lee1; and J.-G. Shin1,2 1 Inje University College of Medicine, Busan, South Korea; and 2 Inje University Busan Paik Hospital, Busan, South Korea CYP4F11, together with CYP4F2, plays an important role in the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. We identified 21 variants by whole exome sequencing, including 4 non-synonymous variants in Korean subjects. The proteins of the wild-type CYP4F11 and the four coding variants (C276R, D315N, D374Y, and D446N) were expressed in Escherichia coli DH5α cells and purified with cytochrome P450-specific carbon monoxide difference spectra. Wild-type CYP4F2 was also expressed and purified to compare its activity with the CYP4F11 wild-type. Wildtype CYP4F11 exhibited the highest maximal clearance for erythromycin N-demethylase activity followed by the variants D374Y, D446N, C276R, and D315N. In particular, the CYP4F11 D315N protein showed about 50% decrease in intrinsic clearance compared to the wild type. The ability of wild-type CYP4F11 and the variants to synthesize 20-HETE from arachidonic acid was similar; the CYP4F11 D315N variant, however, showed only 68% of wild-type activity. Furthermore, the ability of CYP4F2 to synthesize 20-HETE was 1.7-fold greater than that of CYP4F11. Overall, our results suggest that the metabolism of CYP4F11 substrates may be reduced in individuals carrying the CYP4F11 D315N genetic variant, and individuals carrying the common D446N CYP4F11 variant likely exhibit comparable 20-HETE synthesis as individuals expressing wild-type CYP4F11.
New Drug Interaction: Clopidogrel Associated with Paclitaxel Induced Neuropathy in Cancer Patients T.K. Bergmann1,2; K. Agergaard3; M. Mau-Sørensen4; T.B. Stage5; T.L. Jørgensen1; R.E. Hassel6; K.D. Steffensen7; J.W. Pedersen8; M.L.H. Milo9; S.H. Poulsen4; A. Pottegård3; J. Hallas3; and K. Brosen3 1 Odense University Hospital, Odense, Denmark; 2Hospital of South West Denmark, Esbjerg, Denmark; 3University of Southern Denmark, Odense, Denmark; 4Copenhagen University Hospital, Copenhagen, Denmark; 5University of California, San Francisco, San Francisco, California; 6Aarhus University Hospital, Aarhus, Denmark; 7Lillebaelt Hospital, Vejle, Denmark; 8Copenhagen University Hospital, Herlev, Denmark; and 9Aalborg University Hospital, Aalborg, Denmark Background: The recent observation that clopidogrel acyl-β -D-glucuronide increases repaglinide area under the curve
August 2017
2-5 fold via CYP2C8 inhibition gave rise to the hypothesis that clinical relevant CYP2C8 mediated drug-drug-interaction occur between clopidogrel and paclitaxel. To test this hypothesis we performed a retrospective comparison of paclitaxel toxicity in patients treated with clopidogrel and low dose aspirin in breast cancer, ovarian cancer and other malignancies. Methods: The paclitaxel cohort was identified using databases from Danish hospitals and the National Database of Reimbursed Prescriptions. Patients with an active clopidogrel prescription were matched to patients with an active low dose aspirin prescription. Clinical oncologists reviewed patient records and recorded neuropathy and other toxicities. Tes tes tes. Results: The paclitaxel cohort included 7,730 patients of which 48 were exposed to clopidogrel and 85 patients exposed to low dose aspirin were included as controls. The overall hazard ratio of neuropathy associated with clopidogrel use by a cumulative dose of 1500 mg paclitaxel was 1.7 (95% CI, 0.9-3.0) compared to controls using low dose aspirin. This increased risk was accentuated in patients treated with high dose paclitaxel where the adjusted hazard ratio increased to 2.3 (95% CI, 1.1-4.5). Conclusions: Clopidogrel use is associated with an increased risk of paclitaxel induced eripheral sensory neuropathy.
The Influence of Drug Properties and Host Factors on Delayed Onset in Hepatotoxicity A. Gonzalez-Jimenez1; M. Chen2; K. McEuen2; J. Sanabria-Cabrera1; M. Slim1; C. Stephens1; A. Suzuki3; R.J. Andrade1; and M.I. Lucena1 1 IBIMA, H. Virgen de la Victoria, Universidad de Malaga, CIBERehd, Malaga, Spain; 2National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas; and 3University of Arkansas for Medical Sciences, Little Rock, Arkansas Background: Most drug-induced liver injury (DILI) patients develop symptoms while on drug treatments; however in some instances DILI develops after drug cessation. The reasons behind this delayed onset are currently unknown. In this study we aimed to determine drug-properties and host-factors potentially involved in DILI with delayed onset. Methods: 413 DILI cases from the Spanish DILI Registry were classified according to time of first symptom appearance, during (no delay onset, NDO) or after (delay onset, DO) causative agent treatment. The drugs were divided into two groups: drugs with (WP) or without potential (WOP) to induce delayed onset. Only oral drugs with at least three cases in the registry were selected. Amoxicillin-clavulanate (AC) cases were analyzed independently. Results: A total of 11 WP and 33 WOP drugs were found, corresponding to 204 and 209 cases, respectively. Ninety-four (46%) cases, of which 83% were due to AC, presented DO between 2-52 days after treatment cessation. The WP drug cases, omitting AC cases, showed shorter duration of treatment (11 vs 54 days, p= 0.0001), time to onset (14 vs 40 days, p= 0.0001) and higher mean dosage (744 vs 374 mg, p= 0.0001) than the cases induced by WOP drugs. The DO cases showed lower incidence of comorbidities (p= 0.0001). In terms of drug properties, the WP drugs showed lower ratio of hepatic metabolism (p= 0.0190) and higher proportion of parental drug excretion (p= 0.0015). The interactions analyzed showed that drugs with mitochondrial liability have stronger effect on delayed onset in younger patients, females and absence of cardiac diseases. Conclusions: Delayed onset potential appears associated with higher drug dose, shorter treatment and less comorbidities. The fact that
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