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- Aziz, Mohd Yusmaidie, 1984, et al.
(author)
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Inhibition of CYP3A by Antimalarial Piperaquine and Its Metabolites in Human Liver Microsomes With IVIV Extrapolation
- 2018
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In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549. ; 107:5, s. 1461-1467
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Journal article (peer-reviewed)abstract
- The potential of the antimalarial piperaquine and its metabolites to inhibit CYP3A was investigated in pooled human liver microsomes. CYP3A activity was measured by liquid chromatography-tandem mass spectrometry as the rate of 1'-hydroxymidazolam formation. Piperaquine was found to be a reversible, potent inhibitor of CYP3A with the following parameter estimates (%CV): IC50 = 0.76 mu M(29), K-i = 0.68 mu M (29). In addition, piperaquine acted as a time-dependent inhibitor with IC50 declining to 0.32 mu M (28) during 30-min pre-incubation. Time-dependent inhibitor estimates were k(inact) = 0.024 min(-1) (30) and K-I = 1.63 mu M(17). Metabolite M2 was a highly potent reversible inhibitor with estimated IC50 and K-i values of 0.057 mu M (17) and 0.043 mu M (3), respectively. M1 and M5 metabolites did not show any inhibitory properties within the limits of assay used. Average (95th percentile) simulated in vivo areas under the curve of midazolam increased 2.2-fold (3.7-fold) on the third which is the last day of piperaquine dosing, whereas for its metabolite M2, areas under the curve of midazolam increased 7.7-fold (13-fold). (C) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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| 2. |
- Aziz, Mohd Yusmaidie, 1984, et al.
(author)
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LC-MS/MS quantitation of antimalarial drug piperaquine and metabolites in human plasma
- 2017
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In: Journal of chromatography. B. - : Elsevier BV. - 1570-0232. ; 1063, s. 253-258
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Journal article (peer-reviewed)abstract
- Purpose: This study aimed to develop a sensitive, quantitative assay for the antimalarial piperaquine (PQ) and its metabolites M1 and M2 in human plasma. Results: Analytes were gradiently separated on a C18 column and detected with a Sciex API 4000 MS/MS with an ESI source operated in the positive ion mode with deuterated PQ as internal standard. The response was linear in the range 3.9-2508 nM with a runtime of 7.0 min per sample. The method was applied to clinical samples from healthy volunteers. Conclusion: This LC-MS/MS method for the simultaneous quantitation of PQ and two of its metabolites in plasma may prove helpful for assessment of metabolite safety issues in vivo.
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| 3. |
- Aziz, Mohd Yusmaidie, 1984
(author)
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Piperaquine and Metabolites - Bioanalysis and Pharmacokinetics
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Antimalarial piperaquine (PQ) is currently used as a partner drug with dihydroartemisinin (DHA), exhibiting high cure rates (>95%) for P. falciparum. Despite its raising usage worldwide with DHA, PQ is synthetically developed outside of big pharma pipelines. Thus, there is potentially some scientific gap in the information regarding disposition of the drug not being systematically established. This thesis comprised studies on bioanalysis- (Paper I), CYP3A4/5 inhibitory potential- (Paper II), protein binding- (Paper III) and pharmacokinetics (PK) of piperaquine and its metabolites (Paper IV) with intention of filling these scientific gaps. PQ in earlier studies metabolized to two main urinary metabolites, M1 which is a carboxylic acid cleavage product and M2, the mono N-oxide of PQ. PQ and M2 were found as potent CYP3A inhibitors whereby M2 showed greater inhibition in vitro. Simulation of PQ inhibitory effect, predicted the drug-drug interaction (DDI) between PQ and co-administered midazolam in healthy subjects during antimalarial PQ treatment. Bioanalytical method was developed using a highly sensitive analytical instrument, LC-MS/MS to determine PQ and its metabolites in human plasma. The simultaneous quantitation method of PQ and metabolites was developed and validated for the first time based on the FDA guidelines. The method was applied for PK studies of PQ and metabolites after oral administration of single and escalating dose regimen of Artekin® (DHA-PQ) in Vietnamese healthy subjects. PQ exhibited dose- and time independent kinetics. M2 was found to be circulating metabolites in plasma while M1 was hardly detected. Plasma protein binding of PQ and its metabolites were studied in vitro whereby PQ was extensively bound to plasma proteins with higher affinity towards AGP protein than to the albumin while metabolites, exhibited a much lower degree of binding. Unbound fractions of PQ and metabolites were successfully determined in human plasma by ultrafiltration. Generally, the utmost contribution of this thesis is the application of bioanalysis method to quantitate the antimalarial PQ and its metabolites for pharmacokinetics including CYPs- and protein binding studies. As other antimalarials, PQ nowadays should be carefully evaluated for its treatment benefit and risk potential considering the challenge of increasing antimalarial resistance. Furthermore, DHA-PQ is suggested for mass-drug-administration (MDA) to eliminate malaria in Sub-Saharan Africa.
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