in silico modelling;
pharmacokinetics;
physicochemical properties;
physiological model;
tissue distribution;
D O I:
10.1007/s11095-006-9210-3
中图分类号:
O6 [化学];
学科分类号:
0703 ;
摘要:
Purpose. To use recently developed mechanistic equations to predict tissue-to-plasma water partition coefficients (Kpus), apply these predictions to whole body unbound volume of distribution at steady state (Vu(ss)) determinations, and explain the differences in the extent of drug distribution both within and across the various compound classes. Materials and Methods. Vu(ss) values were predicted for 92 structurally diverse compounds in rats and 140 in humans by two approaches. The first approach incorporated Kpu values predicted for 13 tissues whereas the second was restricted to muscle. Results. The prediction accuracy was good for both approaches in rats and humans, with 64-78% and 82-92% of the predicted Vu(ss) values agreeing with in vivo data to within factors of +/- 2 and 3, respectively. Conclusion. Generic distribution processes were identified as lipid partitioning and dissolution where the former is higher for lipophilic unionised drugs. In addition, electrostatic interactions with acidic phospholipids can predominate for ionised bases when affinities (reflected by binding to constituents within blood) are high. For acidic drugs albumin binding dominates when plasma protein binding is high. This ability to explain drug distribution and link it to physicochemical properties can help guide the compound selection process.
机构:
Department of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, ChennaiDepartment of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai
Navina B.K.
Velmurugan N.K.
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机构:
Department of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, ChennaiDepartment of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai
Velmurugan N.K.
Senthil Kumar P.
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机构:
Centre for Pollution Control and Environmental Engineering, School of Engineering and Technology, Pondicherry University, Puducherry, KalapetDepartment of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai
Senthil Kumar P.
Rangasamy G.
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机构:
School of Engineering, Lebanese American University, Byblos
University Centre for Research and Development & Department of Civil Engineering, Chandigarh University, Gharuan, Punjab, MohaliDepartment of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai
Rangasamy G.
Palanivelu J.
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机构:
Department of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, ChennaiDepartment of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai
Palanivelu J.
Thamarai P.
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机构:
Department of Biotechnology, Saveetha School of Engineering, SIMATS, ChennaiDepartment of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai
Thamarai P.
Vickram A.S.
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h-index: 0
机构:
Department of Biotechnology, Saveetha School of Engineering, SIMATS, ChennaiDepartment of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai
Vickram A.S.
Saravanan A.
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机构:
Department of Biotechnology, Saveetha School of Engineering, SIMATS, ChennaiDepartment of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai
Saravanan A.
Shakoor A.
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机构:
Hawkesbury Institute for the Environment, West Sydney University, Penrith, 2751, NSWDepartment of Biotechnology, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai
机构:
NOAA, Natl Marine Fisheries Serv, Alaska Fisheries Sci Ctr, 7600 Sand Point Way NE,Bldg 4, Seattle, WA 98115 USANOAA, Natl Marine Fisheries Serv, Alaska Fisheries Sci Ctr, 7600 Sand Point Way NE,Bldg 4, Seattle, WA 98115 USA
Ormseth, Olav A.
Baker, Matthew M.
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机构:
North Pacific Res Board, 1007 W 3rd Ave 100, Anchorage, AK 99501 USANOAA, Natl Marine Fisheries Serv, Alaska Fisheries Sci Ctr, 7600 Sand Point Way NE,Bldg 4, Seattle, WA 98115 USA
Baker, Matthew M.
Hopcroft, Russell R.
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机构:
Coll Fisheries & Ocean Sci, Inst Marine Sci, 120 ONeill, Fairbanks, AK 99775 USANOAA, Natl Marine Fisheries Serv, Alaska Fisheries Sci Ctr, 7600 Sand Point Way NE,Bldg 4, Seattle, WA 98115 USA
Hopcroft, Russell R.
Ladd, Carol
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h-index: 0
机构:
NOAA, PMEL, 7600 Sand Point Way, Seattle, WA 98115 USANOAA, Natl Marine Fisheries Serv, Alaska Fisheries Sci Ctr, 7600 Sand Point Way NE,Bldg 4, Seattle, WA 98115 USA
Ladd, Carol
Mordy, Calvin W.
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机构:
NOAA, PMEL, 7600 Sand Point Way, Seattle, WA 98115 USANOAA, Natl Marine Fisheries Serv, Alaska Fisheries Sci Ctr, 7600 Sand Point Way NE,Bldg 4, Seattle, WA 98115 USA
Mordy, Calvin W.
Moss, Jamal H.
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机构:
NOAA, Auke Bay Labs, Alaska Fisheries Sci Ctr, NMFS, 17109 Point Lena Loop Rd, Juneau, AK 99801 USANOAA, Natl Marine Fisheries Serv, Alaska Fisheries Sci Ctr, 7600 Sand Point Way NE,Bldg 4, Seattle, WA 98115 USA
Moss, Jamal H.
Mueter, Franz J.
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h-index: 0
机构:
Univ Alaska Fairbanks, Coll Fisheries & Ocean Sci, Dept Fisheries, 17101 Point Lena Loop Rd, Juneau, AK 99801 USANOAA, Natl Marine Fisheries Serv, Alaska Fisheries Sci Ctr, 7600 Sand Point Way NE,Bldg 4, Seattle, WA 98115 USA
Mueter, Franz J.
Shotwell, S. Kalei
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h-index: 0
机构:
NOAA, Auke Bay Labs, Alaska Fisheries Sci Ctr, NMFS, 17109 Point Lena Loop Rd, Juneau, AK 99801 USANOAA, Natl Marine Fisheries Serv, Alaska Fisheries Sci Ctr, 7600 Sand Point Way NE,Bldg 4, Seattle, WA 98115 USA
Shotwell, S. Kalei
Strom, Suzanne L.
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h-index: 0
机构:
Western Washington Univ, Shannon Point Marine Ctr, 1900 Shannon Point Rd, Anacortes, WA 98221 USANOAA, Natl Marine Fisheries Serv, Alaska Fisheries Sci Ctr, 7600 Sand Point Way NE,Bldg 4, Seattle, WA 98115 USA