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Significant Intestinal Excretion, One Source of Variability in Pharmacokinetics of COL-3, a Chemically Modified Tetracycline

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Purpose.

This study was undertaken to examine the disposition of COL-3, a chemically modified tetracycline, in order to elucidate its major route of elimination as one possible source of the variability in pharmacokinetics of COL-3 in vivo.

Methods.

The disposition profile of COL-3 in vivo was assessed by examining the urinary and fecal excretion of the unchanged drug and/or its metabolites in rats after single intravenous and oral administration. The biliary excretion of COL-3 administered orally in bile duct-cannulated rats was also examined. In addition, plasma protein binding and cytochromes P450-mediated metabolism were explored along with erythrocyte partitioning in vivo. Furthermore, transport of COL-3 across Caco-2 monolayers was performed to elucidate the mechanism of intestinal excretion of COL-3 in vivo.

Results.

COL-3 was extensively bound to plasma protein in rat (98%) and human plasma (95%). The affinity of rat blood cells for COL-3, as measured by the ratio of drug concentration in blood cells to that unbound in plasma, was about 36. Of the single intravenous and oral doses, less than 0.2% and 0.03% were excreted unchanged in rat urine, respectively; while 32.1 ± 9.9% and 38.8 ± 6.1% were recovered unchanged in rat feces, respectively, within 48 h postdosing. Of the oral dose, 1.36 ± 0.66% and 2.97 ± 0.88% were excreted in rat bile as the unchanged COL-3 and the total of COL-3 and its glucuronide conjugate, respectively, within 24 h after dosing. COL-3 had insignifi cant cytochrome P450-mediated metabolism but underwent phase II metabolism (i.e., glucuronidation) in a minor quantity. COL-3 was not a substrate of P-glycoprotein. Its transport across Caco-2 monolayers was significantly affected by protein binding and pH.

Conclusions.

Intestinal excretion, a route different from biliary excretion, is the major route of elimination for COL-3 in rats. Variability in intestinal excretion, due to extreme variable intestinal contents (food and digestive fluids), could be one source of variability in COL-3 pharmacokinetics in vivo in addition to the dissolution rate-limited absorption.

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Abbreviations

AP:

apical

BL:

basolateral

BSA:

bovine serum albumin

CMC:

carboxylmethyl cellulose sodium

DMSO:

dimethyl sulfoxide

FBS:

fetal bovine serum

HBSS:

Hank’s Balanced Salt Solution

HEPES:

N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid

HPLC:

high-performance liquid chromatography

MEM:

Minimum Essential Medium

MMP:

matrix metalloproteinase

MWCO:

molecular weight cutoff

NADP+:

β-nicotinamide adenine dinucleotide phosphate

Papp:

apparent permeability coefficient

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Authors and Affiliations

  1. Department of Pharmacy, National University of Singapore, Singapore, 117543, Republic of Singapore

    Jing Li, Shufeng Zhou & Eli Chan

  2. Laboratory of Molecular Endocrinology, National Cancer Centre, Singapore, 169610, Republic of Singapore

    Hung Huynh

  3. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, 21231, USA

    Jing Li

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  1. Jing Li
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Correspondence to Eli Chan.

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Li, J., Zhou, S., Huynh, H. et al. Significant Intestinal Excretion, One Source of Variability in Pharmacokinetics of COL-3, a Chemically Modified Tetracycline. Pharm Res 22, 397–404 (2005). https://doi.org/10.1007/s11095-004-1877-8

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