Dataset Information

Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate.

ABSTRACT: Carboxylesterase 1 (CES1) metabolizes methylphenidate and other drugs. CES1 gene variation only partially explains pharmacokinetic (PK) variability. Biomarkers predicting the PKs of drugs metabolized by CES1 are needed. We identified lipids in plasma from 44 healthy subjects that correlated with CES1 activity as determined by PK parameters of methylphenidate including a ceramide (q value?=?0.001) and a phosphatidylcholine (q value?=?0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value?=?0.040) and several high polyunsaturated fatty acid lipids (PUFAs). The half-maximal inhibitory concentration (IC50 ) values of chenodeoxycholate and taurocholate were 13.55 and 19.51 ?M, respectively, consistent with a physiological significance. In silico analysis suggested that bile acid inhibition of CES1 involved both binding to the active and superficial sites of the enzyme. We initiated identification of metabolites predicting PKs of drugs metabolized by CES1 and suggest lipids to regulate or be regulated by this enzyme.

SUBMITTER: Kaddurah-Daouk R

PROVIDER: S-EPMC6118295 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate.

Kaddurah-Daouk Rima R Hankemeier Thomas T Scholl Elizabeth H EH Baillie Rebecca R Harms Amy A Stage Claus C Dalhoff Kim P KP Jűrgens Gesche G Taboureau Olivier O Nzabonimpa Grace S GS Motsinger-Reif Alison A AA Thomsen Ragnar R Linnet Kristian K Rasmussen Henrik B HB

CPT: pharmacometrics & systems pharmacology 20180801 8

Carboxylesterase 1 (CES1) metabolizes methylphenidate and other drugs. CES1 gene variation only partially explains pharmacokinetic (PK) variability. Biomarkers predicting the PKs of drugs metabolized by CES1 are needed. We identified lipids in plasma from 44 healthy subjects that correlated with CES1 activity as determined by PK parameters of methylphenidate including a ceramide (q value = 0.001) and a phosphatidylcholine (q value = 0.005). Carriers of the CES1 143E allele had decreased methylph ...[more]

PMID: 30169917

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Project description:Purpose/backgroundThe asenapine transdermal system (HP-3070) is the first antipsychotic patch approved in the United States for treatment of adults with schizophrenia.Methods/proceduresThree phase 1, open-label, randomized studies characterized the pharmacokinetic (PK) profile of HP-3070 by assessing its relative bioavailability compared with sublingual asenapine, its single-/multiple-dose PK and dose proportionality, and the effects of application site, ethnicity, and external heat on bioavailability. Two studies were conducted in healthy subjects, and 1 was conducted in adults with schizophrenia.Findings/resultsDuring single HP-3070 administration, asenapine concentrations increased gradually over approximately 12 hours and remained steady until the patch was removed 24 hours after application. Asenapine area under the curve values at HP-3070 3.8 and 7.6 mg/24 hours doses were similar to those for sublingual asenapine 5 and 10 mg twice-daily doses, respectively, whereas peak exposure (maximum observed plasma concentration) was significantly lower. During daily application of HP-3070, steady-state PK was reached within approximately 72 hours after initiating daily dosing and was characterized by peak-to-trough asenapine plasma concentration ratio of approximately 1.5. HP-3070 PK was dose proportional in the dose range studied, not affected by administration site, and similar across the studied ethnic groups. Application of external heat increased the rate of asenapine absorption (time to reach maximum observed plasma concentration) but did not significantly affect peak and total exposure.Implications/conclusionsHP-3070 exhibited a dose-dependent PK profile unaffected by site of administration or ethnicity. HP-3070 showed a predictable absorption profile with limited variability, with an area under the curve similar to that of sublingual asenapine. Based on these PK metrics, HP-3070 steadily delivers asenapine with lower peaks and troughs than sublingual administration of asenapine.

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Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate.

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Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate.

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