Repaglinide

O OH

N O
H
N

Chemical name: (S)-(+)-2-Ethoxy-4-[2-(3-methyl-1-[2-(piperidin-1-yl)

phenyl]butylamino)-2-oxoethyl]benzoic acid
CAS number: 135062-02-1
Molecular formula: C27 H36 N2 O4
Molecular mass (g mol−1 ): 452.6
InChI: 1S/C27H36N2O4/c1-4-33-25-17-20(12-13-22(25)27(31)32)
18-26(30)28-23(16-19(2)3)21-10-6-7-11-24(21)29-14-8-5-9-15-29/
h6-7,10-13,17,19,23H,4-5,8-9,14-16,18H2,1-3H3,(H,28,30)(H,31,32)/
t23-/m0/s1
InChIKey: FAEKWTJYAYMJKF-QHCPKHFHSA-N

Biological activity

Repaglinide (brand names: Prandin, GlucoNorm, NovoNorm, Sureposr, etc.) is a

short-acting antidiabetic drug. It lowers blood glucose by stimulating the release
of insulin from the pancreas. It is used in type II diabetic patients to normalize
postprandial hyperglycemia.

In vitro metabolism

The in vitro metabolism of [14 C]-repaglinide (1) was investigated in human liver
microsomes (HLMs) and recombinant cytochrome P450s (CYPs). Metabolites were

Handbook of Metabolic Pathways of Xenobiotics, First Edition.

Edited by Philip W. Lee, Hiroyasu Aizawa, Lawrence L. Gan, Chandra Prakash, and Dafang Zhong.
© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.
 2

O OH

OH O O
O O
Repaglinide

O OH O OH
O O OH
OH N O
N O N O
H H
H
N+ N
N 9 7 8

O O O
HO
O OH O OH O OH

N OH N O N O
H H H
N N N
5 1 6

O O O

O OH O OH O OH

N O N O N O
H H H
NH2 2 NH O N

OH
3 OH 4

Scheme 1 In vitro metabolic pathway of repaglinide (1).

 Repaglinide 3

measured by high-performance liquid chromatography (HPLC) with online radio-

chemical detection and identified by liquid chromatography–mass spectrometry
(LC-MS) and LC-MS-nuclear magnetic resonance (NMR). Five oxidative metabo-
lites, including an aromatic amine (2) and a dicarboxylic acid (3), both formed by
the opening of the piperidine ring; 4 yielded by hydroxylation of the piperidine
ring; 5 yielded by O-deethylation; and 6 yielded hydroxylation on the isopropyl
moiety. Metabolites 2 and 4 were the primary compounds found in HLMs. CYP2C8
catalyzed the formation of the major metabolite 4, and minor metabolites 2 and 6.
The major metabolite generated by CYP3A4 was 2, metabolites 3, 5, and 6 were
also detected.1
Metabolism of [3 H]-repaglinide in HLMs, human liver S9, human hepatocytes
and recombinant UDP-glucuronosyltransferases (UGTs), and CYPs were also stud-
ied. In addition to 2–6, two additional oxidative dehydrogenation metabolites (7
and 8) were found in HLMs. CYP3A4 mainly catalyzed the biotransformation of 1
to an intermediate (iminium or an aldehyde), which could be further oxidized by an
unidentified cytosolic enzyme to 3. Incubation of [3 H]-repaglinide (0.5 μM) with

O OH
O O O
OH
O O S
O N OH
H
O O OH
N O
OH H
N O
H N
N 9 10

O
O O
O OH
O OH O OH
N O
N OH N O H
H H
N
N N
5 1
4
OH

O
O
O OH
O OH
N O
N O H
H
NH O
NH2
OH
2 3

Scheme 2 In vivo metabolic pathway of repaglinide (1).

4 Repaglinide

human hepatocytes yielded 3 (11%), 4 (13%), and an acylglucuronide of repaglin-

ide 9 (12%) as the major metabolites. UGT1A1 catalyzed the formation of 9.2 The
in vitro metabolic pathway of repaglinide is shown in Scheme 1.

In vivo metabolism
After oral or intravenous (i.v.) administration of [14 C]-repaglinide (1), the metabolic
profiles in plasma, urine, and bile or feces of humans, cynomolgus monkeys,
dogs, rabbits, rats, and mice were analyzed using radio-HPLC and MS. Extensive
metabolism was observed. Metabolites 2, 3, 4, and 5, acylglucuronide conjugate
9, and tauride conjugate 10 were detected. None of these metabolites exhibited
glucose-lowering effect. Compounds 2 and 3 were the major metabolites detected
in humans, monkeys, and rabbits, whereas 3 and 9 were major metabolites in dogs
and rats.
Metabolism and excretion of [14 C]-repaglinide in healthy male volunteers were
investigated following multiple oral dosing of 2 mg (50 μCi).3 Metabolic profile
of 1 in plasma, urine, and feces was determined by HPLC with fraction collection
followed by liquid scintillation counting. The parent compound accounted for 61%
of the total radioactivity in plasma, followed by the major metabolite 3 (piperidine
ring opening, 11%) and minor metabolites 2, 4, 5, 9, and 10. Metabolite 3 was
the major metabolite in feces, with metabolites 2, 4, 5, 9, and 10 as minor prod-
ucts. Metabolites 2 (24%) and 3 (22%) were the major urinary metabolites with
metabolites 4, 5, 9, and 10 as minor products.3 The in vivo metabolic pathway of
repaglinide is shown in Scheme 2.

Data compiled by Juefang Ding

Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai, People’s Republic of China

References
1. T.B. Bidstrup, I. Bjornsdottir, U.G. Sidelmann, et al. CYP2C8 and CYP3A4 are the prin-
cipal enzymes involved in the human in vitro biotransformation of the insulin secretagogue
repaglinide. Br. J. Clin. Pharmacol. 2003, 56, 305.
2. J.P. Gan, W.Q. Chen, H. Shen, et al. Repaglinide–gemfibrozil drug interaction: inhibition
of repaglinide glucuronidation as a potential additional contributing mechanism. Br. J. Clin.
Pharmacol. 2010, 70, 870.
3. P.N. van Heiningen, V. Hatorp, K. Kramer Nielsen, et al. Absorption, metabolism and excre-
tion of a single oral dose of (14)C-repaglinide during repaglinide multiple dosing. Eur. J. Clin.
Pharmacol. 1999, 55, 521.