Synthesis and in vitro characterization of drug conjugates of l-carnitine as potential prodrugs that target human Octn2 Lei Diao, James E. Polli Journal.

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Synthesis and in vitro characterization of drug conjugates of l-carnitine as potential prodrugs that target human Octn2 Lei Diao, James E. Polli Journal of Pharmaceutical Sciences Volume 100, Issue 9, Pages 3802-3816 (September 2011) DOI: 10.1002/jps.22557 Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Scheme 1 Synthesis of valproyl–l-carnitine and ketoprofen–l-carnitine. Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Scheme 2 Synthesis of naproxen–l-carnitine. Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Scheme 3 Synthesis of ketoprofen–glycolic acid–l-carnitine. Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Scheme 4 Synthesis of ketoprofen–glycine–l-carnitine. Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Figure 1 Structures of the prodrugs. (a) Valproyl–l-carnitine, (b) naproxen–l-carnitine, (c) ketoprofen–l-carnitine, (d) ketoprofen–glycolic acid–l-carnitine, and (e) ketoprofen–glycine–l-carnitine. Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Figure 2 Inhibition of l-carnitine uptake into human organic cation/carnitine transporter–Madin–Darby canine kidney cells by (a) valproyl–l-carnitine, (b) naproxen–l-carnitine, and (c) ketoprofen–l-carnitine. Error bars denote SEM. Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Figure 3 Uptake of valproyl–l-carnitine, naproxen–l-carnitine, and ketoprofen–l-carnitine into human organic cation/carnitine transporter–Madin–Darby canine kidney cells in the presence and absence of sodium. (a) Valproyl–l-carnitine uptake was greater in Hanks balanced salt solution (HBSS) than in sodium-free buffer (SFB), (b) naproxen–l-carnitine uptake was greater in HBSS than in SFB, (c) ketoprofen–l-carnitine uptake was greater in HBSS than in SFB. Error bars denote SEM. Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Figure 4 Inhibition of naproxen–l-carnitine or ketoprofen–l-carnitine uptake into human organic cation/carnitine transporter–Madin–Darby canine kidney (hOCTN2–MDCK) cells by l-carnitine. (a) Inhibition of naproxen–l-carnitine uptake (50 μM) into hOCTN2–MDCK cells by 50 and 100 μM l-carnitine, (b) inhibition of ketoprofen–l-carnitine uptake (50 μM) into hOCTN2–MDCK cells by 0–1000 μM l-carnitine. *, p < 0.05 compared with control in the absence of l-carnitine. Error bars denote SEM. Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Figure 5 In vitro metabolic stabilities of naproxen–l-carnitine and ketoprofen–l-carnitine. (a) Stability of naproxen–l-carnitine (1 μM) in rat plasma and porcine liver esterase solution (50 units/mL), (b) stability of ketoprofen–l-carnitine (1 μM) in rat plasma, rat kidney homogenate, and rat liver microsome (2 mg/mL). Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Figure 6 In vitro chemical and metabolic stability of ketoprofen–glycolic acid–l-carnitine (5 μM), along with the generation of ketoprofen. Filled circles (•) indicate ketoprofen–glycolic acid–l-carnitine and open circles (○) indicate ketoprofen. (a) Mouse liver S9, (b) mouse plasma, (c) rat plasma, (d) rat kidney homogenate, (e) porcine liver esterase solution, and (f) chemical stability of ketoprofen–glycolic acid–l-carnitine in various buffers. Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions

Figure 7 Inhibition, uptake, and stability profiles of ketoprofen–glycine–l-carnitine. (a) Inhibition of l-carnitine uptake into organic cation/carnitine transporter–Madin–Darby canine kidney (MDCK) cells by ketoprofen–glycine–l-carnitine, (b) uptake of ketoprofen–glycine–l-carnitine into human organic cation/carnitine transporter (hOCTN2)–MDCK cells in the presence and absence of sodium, (c) inhibition of ketoprofen–glycine–l-carnitine uptake (50 μM) into hOCTN2–MDCK cells by 0–1000 μM l-carnitine. *, p < 0.05 compared with control in the absence of l-carnitine. (d) The stability of ketoprofen–glycine–l-carnitine (5 μM) in Hanks balanced salt solution or metabolic buffers. Journal of Pharmaceutical Sciences 2011 100, 3802-3816DOI: (10.1002/jps.22557) Copyright © 2011 Wiley-Liss, Inc. Terms and Conditions