Pharmacokinetic and pharmacodynamic considerations in gene therapy.
During gene therapy the concentration of plasmid DNA or oligonucleotides in the plasma can be quite different from their concentrations in the nucleus or cytosol where they exert their actions. For a better understanding of the apparent discrepancies between pharmacokinetics (PK) and pharmacodynamics (PD), a new concept for intracellular PK with an emphasis on the final efficacy of gene transcription is needed. Here, the conventional PK and intracellular PK and PD of non-viral gene delivery systems are discussed, together with a new concept, referred to as controlled intracellular disposition, which integrates these factors to gain a better understanding of gene expression in the nucleus. The importance of optimizing the system from a transcriptional point of view in the nucleus is also discussed. These new concepts must be integrated to develop an optimized non-viral gene delivery system.
Kamiya
Hiroyuki
H
Laboratory for Molecular, Design of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo City, Hokkaido 060-0812, Japan.
Akita
Hidetaka
H
Harashima
Hideyoshi
H
D001921:Brain / Q000378:metabolism; D004337:Drug Carriers / Q000378:metabolism; D016503:Drug Delivery Systems; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D009841:Oligonucleotides / Q000493:pharmacokinetics*; D010600:Pharmacology; D010957:Plasmids / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D004337:Drug Carriers; D009841:Oligonucleotides