Patrick KS

References (10)

Title : Plasma carboxylesterase 1 predicts methylphenidate exposure: a proof-of-concept study using plasma protein biomarker for hepatic drug metabolism - Shi_2021_Clin.Pharmacol.Ther__
Author(s) : Shi J , Xiao J , Wang X , Jung SM , Bleske BE , Markowitz JS , Patrick KS , Zhu HJ
Ref : Clinical Pharmacology & Therapeutics , : , 2021
Abstract : Hepatic drug-metabolizing enzymes (DMEs) play critical roles in determining the pharmacokinetics and pharmacodynamics of numerous therapeutic agents. As such, noninvasive biomarkers capable of predicting DME expression in the liver have the potential to be used to personalize pharmacotherapy and improve drug treatment outcomes. In the present study, we quantified carboxylesterase 1 (CES1) protein concentrations in plasma samples collected during a methylphenidate (MPH) PK study. CES1 is a prominent hepatic enzyme responsible for the metabolism of many medications containing small ester moieties, including MPH. The results revealed a significant inverse correlation between plasma CES1 protein concentrations and the area under the concentration-time curves (AUCs) of plasma d-MPH (p = 0.014, r = -0.617). In addition, when plasma CES1 protein levels were normalized to the plasma concentrations of 24 liver-enriched proteins to account for potential interindividual differences in hepatic protein release rate, the correlation was further improved (p = 0.003, r = -0.703), suggesting that plasma CES1 protein could explain approximately 50% of the variability in d-MPH AUCs in the study participants. A physiologically based pharmacokinetic (PBPK) modeling simulation revealed that the CES1-based individualized dosing strategy might significantly reduce d-MPH exposure variability in pediatric patients relative to conventional fixed dosing trial and error regimens. This proof-of-concept study indicates that the plasma protein of a hepatic DME may serve as a biomarker for predicting its metabolic function and the pharmacokinetics of its substrate drugs.
ESTHER : Shi_2021_Clin.Pharmacol.Ther__
PubMedSearch : Shi_2021_Clin.Pharmacol.Ther__
PubMedID: 34743324

Title : Potential for Underestimation of d-Methylphenidate Bioavailability Using Chiral Derivatization\/Gas Chromatography - Patrick_2019_Drug.Metab.Dispos_47_764
Author(s) : Patrick KS , Rodriguez W
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 47 :764 , 2019
Abstract : A tenable hypothesis is presented which explains disparities between older oral dl-MPH bioavailability data generated using chiral derivatization-gas chromatography versus more recent findings using chiral liquid chromatography. These disparities persist in current literature. The gas chromatographic methods found that the absolute bioavailability of d-MPH is 23% and that of l-MPH is 5% (i.e., 82% as the active d-isomer), while liquid chromatographic methods consistently report that approximately 99% of circulating MPH is d-MPH. Older methods used perfluoroacylated S-prolyl derivatizing agents which have a history of imprecision due to the susceptibility of the prolyl S-configuration to isomerize to the R-enantiomer. Accordingly, any R-prolyl impurity in the chiral derivatization reagent yields the (R,R,R)-MPH-prolyl diastereomer which, in being related as the opposite enantiomer of (S,S,S)-prolyl-MPH, co-elutes with l-(S,S)-MPH. This results in overestimation of the percent l-MPH at the expense of underestimating d-MPH. Unless compelling reasons exist to justify use of any chiral discriminators, less complex and less costly achiral analysis of plasma MPH appears appropriate for d-MPH quantitation since 99% exists as d-MPH. However, simultaneous plasma monitoring of d-MPH and l-MPH may be warranted when alterations in first-pass hepatic metabolism by carboxylesterase 1 (CES1) occurs. For example, (a) with transdermal dl-MPH delivery; (b) in cases of concomitant dl-MPH and a CES1 inhibitor, e.g., ethanol, which elevates l-MPH and d-MPH concentrations; (d) in forensic studies of intravenous or intranasal dl-MPH abuse; (e) were dl-MPH to be formulated as a free base sublingual product; or (f) as emerging advances in dl-MPH gene-dose effects warrant isomer correlations.
ESTHER : Patrick_2019_Drug.Metab.Dispos_47_764
PubMedSearch : Patrick_2019_Drug.Metab.Dispos_47_764
PubMedID: 31028056

Title : Drug Regimen Individualization for Attention-Deficit\/Hyperactivity Disorder: Guidance for Methylphenidate and Dexmethylphenidate Formulations - Patrick_2019_Pharmacotherapy_39_677
Author(s) : Patrick KS , Radke JL , Raymond JR , Koller L , Nguyen LV , Rodriguez W , Straughn AB
Ref : Pharmacotherapy , 39 :677 , 2019
Abstract : In 2000, the first biphasic modified-release (MR) formulation of methylphenidate (MPH) was approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). An immediate-release (IR) MPH pulse (22% of the dose) facilitates rapid onset of stimulant action, while the remaining MR portion of the dose provides for day-long duration of efficacy. A wide array of oral MR-MPH products has subsequently been approved that also allows for once-daily dosing, though each product is characterized by distinctive exposure time courses. This review compares each member of the current MPH armamentarium to assist in the rational selection of a specific MPH regimen for the individualized treatment of patients with ADHD. The IR portion of biphasic MPH formulations now ranges from 15%, 20%, 22%, 25%, 30%, and 37% IR-MPH, as well as a 50% IR-MPH product whose distinctly pulsatile time course closely resembles that of the pre-century "gold standard" twice-daily IR-MPH regimen. Further, transdermal, suspension, and orally disintegrating tablet products are now available to overcome any solid dosage form swallowing difficulties. Most of these formulations are racemic, though in 2001, a chiral switch drug IR-dexmethylphenidate (dexMPH) was approved, followed by biphasic MR-dexMPH (50% IR) in 2005. New U.S. Food and Drug Administration (FDA) partial area under the curve (pAUC) bioavailability metrics have improved discrimination between specific generic MR-MPH products. This has resulted in two Orange Book MR-MPH products being recoded from "AB" (i.e., meets necessary bioequivalence requirements) to "BX" (i.e., insufficient data to confirm bioequivalence). The metabolic drug interaction between MPH and alcohol, which increases MPH bioavailability, potentiates euphoric effects, and heightens abuse liability, is discussed. This review concludes with brief considerations of pharmacogenomic predictors of ADHD first-line drug selection, carboxylesterase allelic variants influencing interindividual MPH metabolism, and novel MPH formulations in the regulatory pipeline.
ESTHER : Patrick_2019_Pharmacotherapy_39_677
PubMedSearch : Patrick_2019_Pharmacotherapy_39_677
PubMedID: 30351459

Title : Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers - Zhu_2017_J.Clin.Psychopharmacol_37_419
Author(s) : Zhu HJ , Patrick KS , Straughn AB , Reeves OT, 3rd , Bernstein H , Shi J , Johnson HJ , Knight JM , Smith AT , Malcolm RJ , Markowitz JS
Ref : J Clin Psychopharmacol , 37 :419 , 2017
Abstract : BACKGROUND/PURPOSE: Ethanol coadministered with immediate-release dl-methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration (Cmax) of d-MPH 22% and 15%, respectively, and elevates overall drug exposure and psychostimulant effects. We asked the question: Are these ethanol-MPH interactions based more fundamentally on (1) inhibition of postabsorption d-MPH metabolism or (2) acceleration of MPH formulation gastric dissolution by ethanol in the stomach? This was investigated using the pulsatile, distinctly biphasic, spheroidal oral drug absorption systems of dl-MPH and d-MPH.
METHODS: In a randomized, 4-way crossover study, 14 healthy subjects received pulsatile dl-MPH (40 mg) or d-MPH (20 mg), with or without ethanol (0.6 g/kg), dosed 4 hours later. These 4 hours allowed the delayed-release second MPH pulse to reach a more distal region of the gut to preclude gastric biopharmaceutical influences. Plasma was analyzed using a highly sensitive chiral method. Subjective/physiological effects were recorded. FINDINGS/RESULTS: Ethanol increased the second pulse of d-MPH Cmax for dl-MPH by 35% (P < 0.01) and the partial area under the plasma concentration curve from 4 to 8 hours by 25% (P < 0.05). The respective values for enantiopure d-MPH were 27% (P = 0.001) and 20% (P < 0.01). The carboxylesterase 1-mediated transesterification metabolite ethylphenidate served as a biomarker for coexposure. Ethanol significantly potentiated stimulant responses to either formulation. IMPLICATIONS/
CONCLUSIONS: These findings support drug dispositional interactions between ethanol and MPH as dominant over potential biopharmaceutical considerations. Understanding the pharmacology underlying the frequent coabuse of MPH-ethanol provides rational guidance in the selection of first-line pharmacotherapy for comorbid attention-deficit/hyperactivity disorder-alcohol use disorder.
ESTHER : Zhu_2017_J.Clin.Psychopharmacol_37_419
PubMedSearch : Zhu_2017_J.Clin.Psychopharmacol_37_419
PubMedID: 28590363

Title : Ethylphenidate as a Selective Dopaminergic Agonist and Methylphenidate-Ethanol Transesterification Biomarker - Patrick_2014_J.Pharm.Sci_103_3834
Author(s) : Patrick KS , Corbin TR , Murphy CE
Ref : J Pharm Sci , 103 :3834 , 2014
Abstract : We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery, drug interactions, biomarker for dl-methylphenidate (MPH)-ethanol exposure, potentiation of dl-MPH abuse liability, contemporary "designer drug," pertinence to the newer transdermal and chiral switch MPH formulations, as well as problematic internal standard. d-EPH selectively targets the dopamine transporter, whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. This selectivity carries implications for the advancement of tailored attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in the era of genome-based diagnostics. Abuse of dl-MPH often involves ethanol coabuse. Carboxylesterase 1 enantioselectively transesterifies l-MPH with ethanol to yield l-EPH accompanied by significantly increased early exposure to d-MPH and rapid potentiation of euphoria. The pharmacokinetic component of this drug interaction can largely be avoided using dexmethylphenidate (dexMPH). This notwithstanding, maximal potentiated euphoria occurs following dexMPH-ethanol. C57BL/6 mice model dl-MPH-ethanol interactions: an otherwise depressive dose of ethanol synergistically increases dl-MPH stimulation; a substimulatory dose of dl-MPH potentiates a low, stimulatory dose of ethanol; ethanol elevates blood, brain, and urinary d-MPH concentrations while forming l-EPH. Integration of EPH preclinical neuropharmacology with clinical studies of MPH-ethanol interactions provides a translational approach toward advancement of ADHD personalized medicine and management of comorbid alcohol use disorder. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3834-3842, 2014.
ESTHER : Patrick_2014_J.Pharm.Sci_103_3834
PubMedSearch : Patrick_2014_J.Pharm.Sci_103_3834
PubMedID: 25303048

Title : Isopropylphenidate: an ester homolog of methylphenidate with sustained and selective dopaminergic activity and reduced drug interaction liability - Markowitz_2013_J.Child.Adolesc.Psychopharmacol_23_648
Author(s) : Markowitz JS , Zhu HJ , Patrick KS
Ref : J Child Adolesc Psychopharmacol , 23 :648 , 2013
Abstract : Abstract Objective: The most widely utilized pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD) is the psychostimulant methylphenidate (MPH). Most MPH formulations consist of the racemic mixture of d-threo-(R, R)-MPH and l-threo-(S, S)-MPH isomers. MPH is characterized by its low bioavailability and short half-life (2-3 hours). Additionally, significant inter-individual variability in MPH pharmacokinetics has been consistently documented. Accordingly, efforts have been directed at developing alternatives to MPH as therapeutic agents. A wide range of MPH analogues (dl-alpha-[2-piperidyl]-phenylacetic acid esters) have been synthesized with the dopamine transporter (DAT) and norepinephrine transporter (NET) as principle neuropharmacological targets. The present study investigated the metabolic profiles and pharmacological activity of the isopropyl ester derivative of MPH, dl-isopropylphenidate (IPH), both in vitro and in vivo. Methods: The synthesis, monoaminergic transporter binding, cellular uptake profiles, and assessment of metabolic hydrolysis and transesterification in the presence of ethanol are described using MPH as a comparator. Additionally, an in vivo assessment of IPH stimulant effects (vs. saline) in rats was performed with locomotor activity as a pharmacodynamic outcome. Results: IPH displayed unique pharmacological characteristics including greater DAT than NET binding and cellular uptake activity, and greater resistance to hydrolysis and transesterification via carboxylesterase 1 relative to MPH. Further, sustained psychostimulant properties offer the prospect of an enhanced duration of action. Conclusions: Our findings are consistent with IPH exhibiting attributes distinguishing it from MPH and warranting further study and development of IPH as a novel psychotherapeutic agent.
ESTHER : Markowitz_2013_J.Child.Adolesc.Psychopharmacol_23_648
PubMedSearch : Markowitz_2013_J.Child.Adolesc.Psychopharmacol_23_648
PubMedID: 24261661

Title : Differential influences of ethanol on early exposure to racemic methylphenidate compared with dexmethylphenidate in humans - Patrick_2013_Drug.Metab.Dispos_41_197
Author(s) : Patrick KS , Straughn AB , Reeves OT, 3rd , Bernstein H , Bell GH , Anderson ER , Malcolm RJ
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 41 :197 , 2013
Abstract : Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1-2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44-99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of "high," "good," "like," "stimulated," and overall "effect" were significantly potentiated (P <= 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH. Ethanol increased the d-MPH area under the curve (AUC)(0-inf) by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC(0.5-2 hours) was 2.1 times greater and the time to maximum concentration (T(max)) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability.
ESTHER : Patrick_2013_Drug.Metab.Dispos_41_197
PubMedSearch : Patrick_2013_Drug.Metab.Dispos_41_197
PubMedID: 23104969

Title : Enantiospecific determination of dl-methylphenidate and dl-ethylphenidate in plasma by liquid chromatography-tandem mass spectrometry: Application to human ethanol interactions - Zhu_2011_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_879_783
Author(s) : Zhu HJ , Patrick KS , Markowitz JS
Ref : Journal of Chromatography B Analyt Technol Biomed Life Sciences , 879 :783 , 2011
Abstract : In humans, concomitant DL-methylphenidate (DL-MPH) and ethanol results in the carboxylesterase 1 (hCES1) mediated biotransformation of MPH to the transesterification metabolite DL-ethylphenidate (DL-EPH). The separate enantiomers of MPH and EPH are found at low ng/ml to pg/ml plasma concentrations. Substantial pharmacological differences exist between D- and L-isomers of MPH and EPH, both in terms of pharmacological potencies and receptor selectivity, as well as in pharmacokinetic properties. Accordingly, a sensitive, accurate and precise enantiospecific analytical method is required in order to fully explore pharmacokinetic-pharmacodynamic correlations regarding the MPH-ethanol interaction. The present study describes a novel liquid chromatographic-tandem mass spectrometric method for simultaneous analysis of D- and L-MPH as well as D- and L-EPH concentrations from human plasma. This assay provides baseline resolution of the individual MPH and EPH isomers utilizing a vancomycin-based chiral column. The lower limit of quantification was 0.025 ng/ml for each isomer when extracting 0.5 ml plasma aliquots. Calibration curves were linear over the range from 0.025 ng/ml to 25 ng/ml for all analytes (r(2)>0.995). Assay accuracy and precision were excellent and stability studies and assessment of potential matrix effects contributed to the validation of the method. Application of the method to human plasma samples collected after the administration of dl-MPH with or without ethanol is included, and the implications of this pharmacokinetic drug interaction discussed.
ESTHER : Zhu_2011_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_879_783
PubMedSearch : Zhu_2011_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_879_783
PubMedID: 21402502

Title : Enantiospecific gas chromatographic-mass spectrometric analysis of urinary methylphenidate: implications for phenotyping - LeVasseur_2008_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_862_140
Author(s) : LeVasseur NL , Zhu HJ , Markowitz JS , DeVane CL , Patrick KS
Ref : Journal of Chromatography B Analyt Technol Biomed Life Sciences , 862 :140 , 2008
Abstract : A chiral derivatization gas chromatographic-mass spectrometric (GC-MS) method for urine methylphenidate (MPH) analysis was developed and validated to investigate preliminary findings regarding a novel MPH poor metabolizer (PM). Detection was by electron impact (EI) ionization-selected ion monitoring of the N-trifluoroacetylprolylpiperidinium fragments from MPH and the piperidine-deuterated MPH internal standard. The PM eliminated approximately 70 times more l-MPH in urine (9% of the dose over 0-10h), and approximately 5 times more of the d-isomer (10% of the dose), than the mean values determined from 10 normal metabolizers of MPH. Only minor amounts of the metabolite p-hydroxy-MPH were found in the urine of both the PM and normal metabolizers, while the concentration of MPH lactam was not high enough to be detectable. The described method indirectly gauges the functional carboxylesterase-1 status of patients receiving MPH based on the evaluation of relative urine concentrations of d-MPH:l-MPH. Clinical implications concerning rational drug selection for an identified or suspected MPH PM are discussed.
ESTHER : LeVasseur_2008_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_862_140
PubMedSearch : LeVasseur_2008_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_862_140
PubMedID: 18155648

Title : Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis - Zhu_2008_Am.J.Hum.Genet_82_1241
Author(s) : Zhu HJ , Patrick KS , Yuan HJ , Wang JS , Donovan JL , DeVane CL , Malcolm R , Johnson JA , Youngblood GL , Sweet DH , Langaee TY , Markowitz JS
Ref : American Journal of Human Genetics , 82 :1241 , 2008
Abstract : The human carboxylesterase 1 (CES1) gene encodes for the enzyme carboxylesterase 1, a serine esterase governing both metabolic deactivation and activation of numerous therapeutic agents. During the course of a study of the pharmacokinetics of the methyl ester racemic psychostimulant methylphenidate, profoundly elevated methylphenidate plasma concentrations, unprecedented distortions in isomer disposition, and increases in hemodynamic measures were observed in a subject of European descent. These observations led to a focused study of the subject's CES1 gene. DNA sequencing detected two coding region single-nucleotide mutations located in exons 4 and 6. The mutation in exon 4 is located in codon 143 and leads to a nonconservative substitution, p.Gly143Glu. A deletion in exon 6 at codon 260 results in a frameshift mutation, p.Asp260fs, altering residues 260-299 before truncating at a premature stop codon. The minor allele frequency of p.Gly143Glu was determined to be 3.7%, 4.3%, 2.0%, and 0% in white, black, Hispanic, and Asian populations, respectively. Of 925 individual DNA samples examined, none carried the p.Asp260fs, indicating it is an extremely rare mutation. In vitro functional studies demonstrated the catalytic functions of both p.Gly143Glu and p.Asp260fs are substantially impaired, resulting in a complete loss of hydrolytic activity toward methylphenidate. When a more sensitive esterase substrate, p-nitrophenyl acetate was utilized, only 21.4% and 0.6% catalytic efficiency (V(max)/K(m)) were determined in p.Gly143Glu and p.Asp260fs, respectively, compared to the wild-type enzyme. These findings indicate that specific CES1 gene variants can lead to clinically significant alterations in pharmacokinetics and drug response of carboxylesterase 1 substrates.
ESTHER : Zhu_2008_Am.J.Hum.Genet_82_1241
PubMedSearch : Zhu_2008_Am.J.Hum.Genet_82_1241
PubMedID: 18485328
Gene_locus related to this paper: human-CES1