Full efficacy with no CNS side-effects: unachievable panacea or reality? DMPK considerations in design of drugs with limited brain penetration

被引：20

作者：

Cole, Susan ^{[1
]}

Bagal, Sharan ^{[2
]}

El-Kattan, Ayman ^{[3
]}

Fenner, Katherine ^{[1
]}

Hay, Tanya ^{[1
]}

Kempshall, Sarah ^{[1
]}

Lunn, Graham ^{[2
]}

Varma, Manthena ^{[3
]}

Stupple, Paul ^{[2
]}

Speed, William ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Sandwich, Kent, England

[2] Pfizer Global Res & Dev, Worldwide Med Chenistry, Sandwich, Kent, England

[3] Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Groton, CT USA

来源：

XENOBIOTICA | 2012年 / 42卷 / 01期

关键词：

Peripheral restriction; brain penetration; P-gp; BCRP; polar surface area; CENTRAL-NERVOUS-SYSTEM; GLYCOPROTEIN-MEDIATED EFFLUX; CANCER RESISTANCE PROTEIN; IN-VIVO MICRODIALYSIS; P-GLYCOPROTEIN; ORAL BIOAVAILABILITY; INTESTINAL-ABSORPTION; UNBOUND CONCENTRATION; PEPTIDE TRANSPORTERS; STEADY-STATE;

D O I：

10.3109/00498254.2011.617847

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

1. Optimising drug properties can be an important strategy to limit penetration into the CNS and offers advantages in reducing the risk of undesirable neurological effects 2. When considering the design of these drugs it is important to consider the relative influx and efflux rates at the relevant biological membranes 3. The highest degree of restriction at the brain is probably achievable by utilising active transport to exclude compounds from the brain 4. Affinity for the efflux transporters Pgp and BCRP has been achieved in two in-house chemistry programmes by increasing polar surface area, which resulted in highly orally bioavailable low CNS penetrant compounds in preclinical species

引用

页码：11 / 27

页数：17

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