Pharmacokinetic Concepts in Brain Drug Delivery
This chapter presents the pharmacokinetic principles of blood–brain barrier (BBB) transport and the intra-brain distribution of drugs in order to provide a basis for understanding drug delivery to the brain from a clinically relevant perspective. The most
- PDF / 638,643 Bytes
- 35 Pages / 439.37 x 666.142 pts Page_size
- 12 Downloads / 205 Views
Pharmacokinetic Concepts in Brain Drug Delivery Margareta Hammarlund-Udenaes
Abstract This chapter presents the pharmacokinetic principles of blood–brain barrier (BBB) transport and the intra-brain distribution of drugs in order to provide a basis for understanding drug delivery to the brain from a clinically relevant perspective. The most important concentrations to measure when determining drug distribution are those of the unbound drug, because it is the unbound drug that causes the pharmacological effect by interacting with the target. Therefore, this chapter also discusses the pharmacokinetic basis, the kind of information provided, and the in vivo relevance of the methods used to obtain reliable, therapeutically useful estimates of brain drug delivery. The main factors governing drug distribution to the brain are the permeability of the BBB to the drug (influx clearance), the extent of nonspecific binding to brain tissue, and the efflux clearance of the drug. The ratio of the influx and efflux clearances provides an estimation of the extent of drug equilibration across the BBB, described by Kp,uu,brain. This parameter is important, as active uptake and/or efflux transporters influence the absolute brain concentrations of unbound drug in relation to those in plasma. The advantage of using Kp,uu,brain during the drug discovery process lies in its ability to predict the potential success of drugs intended for action within the brain or, conversely, of those with few or no side effects in the brain. Abrain Aslice Atot.brain_inc_blood AUCtot,brain AUCtot,plasma AUCu,brainISF
Amount of drug per g brain tissue excluding blood Amount of drug per g of brain slice Amount of drug per g brain tissue including blood Area under the total brain concentration–time curve Area under the total plasma concentration–time curve Area under the unbound brain ISF concentration–time curve
M. Hammarlund-Udenaes (*) Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden e-mail: [email protected] M. Hammarlund-Udenaes et al. (eds.), Drug Delivery to the Brain, AAPS Advances in the Pharmaceutical Sciences Series 10, DOI 10.1007/978-1-4614-9105-7_5, © American Association of Pharmaceutical Scientists 2014
127
128
AUCu,plasma BBB BCSFB BBMEC Caco-2 Cbuffer Ci
M. Hammarlund-Udenaes
Area under the unbound plasma concentration–time curve Blood–brain barrier Blood–cerebrospinal fluid barrier Bovine brain microvessel endothelial cells Human epithelial colorectal adenocarcinoma cells Concentration of drug in the buffer (brain slice method) Apparent concentration of drug in a peripheral brain compartment i Total concentration of drug in blood Ctot,blood Ctot.plasma Total concentration of drug in plasma Cu,brainISF Concentration of drug in the brain ISF (by definition unbound) Cu,cell Average concentration of unbound drug in brain cells Cu,plasma Unbound concentration in plasma Cu,ss,plasma Unbound steady-state concentration in plasma Cu,ss,brainISF Unbound steady-state concentration in b
Data Loading...
