title: Single jugular vein cannulated rats may not be suitable for intravenous pharmacokinetic screening of high logP compounds.
abstract: Rat is commonly used for pharmacokinetic screening during pharmaceutical lead optimization. To handle the large number of compounds, rats with a single jugular vein cannulation are commonly utilized for intravenous pharmacokinetic studies, where the same cannula is used both for dose administration and blood sampling. We demonstrate that the single cannula method is not suitable for all compounds, especially for high logP compounds. We propose an alternative dual cannulation technique in which two cannulas are placed in the same jugular vein, thus avoiding an additional surgery. Compounds were administered orally or via intravenous infusion to compare PK parameters, including bioavailability, using both procedures. For itraconazole and amiodarone, known to bind to the cannula, the measured plasma exposures were substantially higher in the single cannulated rats than those from dual cannulated rats. Area under the plasma concentration time curve differed by 79% and 74% for itraconazole and amiodarone, respectively. When compared to the single cannulation approach, clearance, volume of distribution and bioavailability determined by dual cannulation were 39%, 60% and 38% higher for itraconazole, and 46%, 34% and 42% higher for amiodarone, respectively. In contrast, all pharmacokinetic parameters were similar between single and dual-cannulated rats for the hydrophilic compound atenolol. Based on these results, we recommend the use of dual cannulated rats for intravenous pharmacokinetic studies when testing a series of hydrophobic compounds that may be prone to non-specific binding to the cannula. If single cannulated model is selected for pharmacokinetic screening, we recommend a bridging study with dual cannulated rats with representative compounds of a given chemical series.
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Gaud
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India.
authors.forename: Anoop
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India.
authors.forename: Muralikrishna
authors.initials: M
authors.lastname: Matta
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Kole
authors.affiliation: Biopharmaceutics, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Sridhar
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol Myers-Squibb R&D Centre (BBRC), Bristol-Myers Squibb India Pvt. Ltd., Bangalore 560 099, India.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Mandlekar
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Plot 2 & 3, Bommasandra IV Phase, Bangalore 560099, India. Electronic address: vinay.gupta@syngeneintl.com.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Holenarsipur
mesh_terms: D061605:Administration, Intravenous / Q000379:methods; D000284:Administration, Oral; D000638:Amiodarone / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D001800:Blood Specimen Collection / Q000379:methods; D002404:Catheterization / Q000379:methods*; D017964:Itraconazole / Q000493:pharmacokinetics*; D007601:Jugular Veins / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017964:Itraconazole; D000638:Amiodarone
keywords: Amiodarone; Atenolol; Blood sampling methods; Dual cannulation; Itraconazole; Jugular vein; Non-specific binding; Rat pharmacokinetic studies