title: In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1.
abstract: Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Kmvalue of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC50= 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter.
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Y.A.P., A.J.L.,W.F.A., J.W.W., M.P.K., M.A.A.-O., M.I.M., K.M.H.); and Quintiles Transnational, Clinical Pharmacology, Overland Park, Kansas (P.L.) pak_youngeen_anne@lilly.com.
authors.forename: Y Anne
authors.initials: YA
authors.lastname: Pak
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Y.A.P., A.J.L.,W.F.A., J.W.W., M.P.K., M.A.A.-O., M.I.M., K.M.H.); and Quintiles Transnational, Clinical Pharmacology, Overland Park, Kansas (P.L.).
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Long
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Y.A.P., A.J.L.,W.F.A., J.W.W., M.P.K., M.A.A.-O., M.I.M., K.M.H.); and Quintiles Transnational, Clinical Pharmacology, Overland Park, Kansas (P.L.).
authors.forename: William F
authors.initials: WF
authors.lastname: Annes
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Y.A.P., A.J.L.,W.F.A., J.W.W., M.P.K., M.A.A.-O., M.I.M., K.M.H.); and Quintiles Transnational, Clinical Pharmacology, Overland Park, Kansas (P.L.).
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Witcher
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Y.A.P., A.J.L.,W.F.A., J.W.W., M.P.K., M.A.A.-O., M.I.M., K.M.H.); and Quintiles Transnational, Clinical Pharmacology, Overland Park, Kansas (P.L.).
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Knadler
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Y.A.P., A.J.L.,W.F.A., J.W.W., M.P.K., M.A.A.-O., M.I.M., K.M.H.); and Quintiles Transnational, Clinical Pharmacology, Overland Park, Kansas (P.L.).
authors.forename: Mosun A
authors.initials: MA
authors.lastname: Ayan-Oshodi
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Y.A.P., A.J.L.,W.F.A., J.W.W., M.P.K., M.A.A.-O., M.I.M., K.M.H.); and Quintiles Transnational, Clinical Pharmacology, Overland Park, Kansas (P.L.).
authors.forename: Malcolm I
authors.initials: MI
authors.lastname: Mitchell
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Y.A.P., A.J.L.,W.F.A., J.W.W., M.P.K., M.A.A.-O., M.I.M., K.M.H.); and Quintiles Transnational, Clinical Pharmacology, Overland Park, Kansas (P.L.).
authors.forename: Phillip
authors.initials: P
authors.lastname: Leese
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Y.A.P., A.J.L.,W.F.A., J.W.W., M.P.K., M.A.A.-O., M.I.M., K.M.H.); and Quintiles Transnational, Clinical Pharmacology, Overland Park, Kansas (P.L.).
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Hillgren
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000652:urine; D001692:Biological Transport; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000097:blood / Q000652:urine; D003499:Cyclic S-Oxides / Q000097:blood / Q000652:urine; D004347:Drug Interactions; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D000074011:Peptide Transporter 1 / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013379:Substrate Specificity; D000077483:Valacyclovir; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D055815:Young Adult
chemical_list: C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D000074011:Peptide Transporter 1; D011355:Prodrugs; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C000626254:pomaglumetad methionil; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir