Abstract
We present herein a compilation and trend analysis of human i.v. pharmacokinetic data on 670 drugs representing, to our knowledge, the largest publicly available set of human clinical pharmacokinetic data. This data set provides the drug metabolism scientist with a robust and accurate resource suitable for a number of applications, including in silico modeling, in vitro-in vivo scaling, and physiologically based pharmacokinetic approaches. Clearance, volume of distribution at steady state, mean residence time, and terminal phase half-life were obtained or derived from original references exclusively from studies utilizing i.v. administration. Plasma protein binding data were collected from other sources to supplement these pharmacokinetic data. These parameters were analyzed concurrently with a range of simple physicochemical descriptors, and resultant trends and patterns within the data are presented. Our findings with this much expanded data set were consistent with earlier described notions of trends between physicochemical properties and pharmacokinetic behavior. These observations and analyses, along with the large database of human pharmacokinetic data, should enable future efforts aimed toward developing quantitative structure-pharmacokinetic relationships and improving our understanding of the relationship between fundamental chemical characteristics and drug disposition.
Footnotes
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The complete list of compounds with pharmacokinetic data, Chemical Abstracts Services numbers, full references, and comments by the authors of this manuscript are available as an Excel file. A color version of Figs. 2, 5, 9, and 10 is also available in a Word file as Supplemental data.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.020479.
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ABBREVIATIONS: CL, clearance; VD, volume of distribution; VDss, steady-state volume of distribution; PSA, polar surface area; PK, pharmokinetic; DHA, docosahexaenoate; MRT, mean residence time; VDss,u, free volume of distribution at steady-state; CLu, free plasma clearance; fu, free fraction in plasma; BB 83698, N-[(1S)-1-[[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]carbonyl]-2,2-dimethylpropyl]-α-[(formylhydroxyamino)methyl]-(αR)-cyclopentanepropanamide; BMS-214662, 2,3,4,5-tetrahydro-1-(1H-imidazol-5-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-(3R)-1H-1,4-benzodiazepine-7-carbonitrile; CB 10-277, p-(3,3-dimethyl-1-triazeno)benzoic acid; DP-b 99, N,N′-[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[N-(carboxymethyl)-1,1′-bis[2-(octyloxy)ethyl] ester (9CI)-glycine; IVL745, N-[[3-methoxy-4-[[[(2-methylphenyl)amino]carbonyl]amino]phenyl]acetyl]-glycyl-N-[(3,4-dimethoxyphenyl)methyl]-(9CI)-β-alanine; KRN-5500, 4-deoxy-4-[[2-[[2E,4E)-1-oxo-2,4-tetradecadien-1-yl]amino]acetyl]amino]-N-1H-purin-6-yl-l-glycero-β-l-manno-heptopyranosylamine; KW-2170, 5-[(3-aminopropyl)amino]-7,10-dihydroxy-2-[[(2-hydroxyethyl)amino]-methyl]-6H-pyrazolo[4,5,1-de]acridin-6-one; MEN-10755, 7-[[4-O-(3-amino-2,3,6-trideoxy-α-l-lyxo-hexopyranosyl)-2,6-dideoxy-α-l-lyxo-hexopyranosyl]oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxy-9-(hydroxyacetyl)-5,12-naphthacenedione; NK 611, [[2-deoxy-2-(dimethylamino)-4,6-O-(1R)-ethylidene-β-d-glycopyranosyl]oxy]-5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)-furo[3′,4′:6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one; PNU-145156E, 7,7′-[carbonylbis[imino(1-methyl-1H-pyrrole-4,2-diyl)carbonylimino(1-methyl-1H-pyrrole-4,2-diyl)carbonylimino]]bis-1,3-naphthalenedisulfonic acid; RPR 109881A, β-[[(1,1-dimethylethoxy)carbonyl]amino]-α-hydroxy-(1S,2S,4S,7R,8aR,9aS,10aR,12aS,12bR)-7,12a-bis(acetyloxy)-1-(benzoyloxy)-1,3,4,7,8,9,9a,10,10a,12,12a,12b,-dodecahydro-2-hydroxy-5,13,13-trimethyl-8-oxo-2,6-methano-2H-cyclodeca[3,4]cyclopropa[4,5]benz[1,2-b]oxet-4-yl benzenepropanoic acid ester(αR,βS); Sch34343, 3-[[2-[(aminocarbonyl)oxy]ethyl]thio]-6-[(1R)-1-hydroxyethyl]-7-oxo-(5R,6S)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; UK-240,455, N-(6,7-dichloro-1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)-N-(2-hydroxyethyl)-methanesulfonamide.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material. - Received January 16, 2008.
- Accepted April 18, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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