PRINCIPLES OF TOXICOLOGY

38 ABSORPTION, DISTRIBUTION, AND ELIMINATION OF TOXIC AGENTS
TABLE 2.1 Partition Coefficients and Rates of Transfer of Selected Drugs from Plasma
into Cerebrospinal Fluid of Dogs
Heptane–Water
Partition Coefficient of
Nonionized Half-Life of
Drug Form of Drug Transfer Process (min)
Thiopental 3.3 1.4
Aniline 1.1 1.7
Aminopyrine 0.21 2.8
Pentobarbital 0.05 4.1
Antipyrine 0.005 5.8
Barbital 0.002 27
N-Acetyl-4-aminoantipyrine 0.001 58
Sulfaguanidine < 0.001 230
Source: Adapted from Brodie et al. (1960), Table 2.
water-soluble than their larger homologs. If this is the case, they may be able to move through
membrane pores.
Pores are features of all membranes. Their size varies with the nature and function of the membrane.
Cell membranes will not allow passage of water-soluble molecules larger than about 4 × 10 –4 µm in
diameter, while blood capillary walls allow passage of water-soluble molecules up to about 30 × 10 –4
µm in diameter. Even within this size range of large water-soluble compounds, the rate of transcapillary
movement is inversely proportional to molecular radius. Note that the cutoff of 30 × 10 –4 µm excludes
plasma proteins, so that they are retained within the plasma fluid volume.
Degree of Ionization The third important feature of the molecule determining ease of movement
through membranes is its degree of ionization. Electrolytes are ionized at the pH values of body fluids.
With the exception of very small ionized molecules that can pass through membrane pores, only the
nonionized forms of most electrolytes are able to cross membranes. The ionized forms are generally
too large to pass through the aqueous pores, and are insufficiently lipophilic to be transferred by passive
diffusion. The rate of diffusion therefore will depend not only on the amount of an electrolyte present
in the nonionized form but also on the ease with which the nonionized form of the molecule can cross
the membrane, that is, on its molecular size and lipophilicity.
All ionizable acids and bases have a pK a value related to the dissociation constant. The dissociation
constant is always expressed for either acids or bases as an acid dissociation constant, K a :
For acids:
For bases:
Ka = (H+ )(A − )
(HA)
Ka = (H+ )(B)
(HB + )