PRINCIPLES OF TOXICOLOGY - Biology East Borneo

38 ABSORPTION, DISTRIBUTION, AND ELIMINATION OF TOXIC AGENTSTABLE 2.1 Partition Coefficients and Rates of Transfer of Selected Drugs from Plasmainto Cerebrospinal Fluid of DogsHeptane–WaterPartition Coefficient ofNonionizedHalf-Life ofDrug Form of Drug Transfer Process (min)Thiopental 3.3 1.4Aniline 1.1 1.7Aminopyrine 0.21 2.8Pentobarbital 0.05 4.1Antipyrine 0.005 5.8Barbital 0.002 27N-Acetyl-4-aminoantipyrine 0.001 58Sulfaguanidine < 0.001 230Source: 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 throughmembrane 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 indiameter, while blood capillary walls allow passage of water-soluble molecules up to about 30 × 10 –4µm in diameter. Even within this size range of large water-soluble compounds, the rate of transcapillarymovement is inversely proportional to molecular radius. Note that the cutoff of 30 × 10 –4 µm excludesplasma proteins, so that they are retained within the plasma fluid volume.Degree of Ionization The third important feature of the molecule determining ease of movementthrough 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 thenonionized forms of most electrolytes are able to cross membranes. The ionized forms are generallytoo large to pass through the aqueous pores, and are insufficiently lipophilic to be transferred by passivediffusion. The rate of diffusion therefore will depend not only on the amount of an electrolyte presentin the nonionized form but also on the ease with which the nonionized form of the molecule can crossthe membrane, that is, on its molecular size and lipophilicity.All ionizable acids and bases have a pK avalue related to the dissociation constant. The dissociationconstant is always expressed for either acids or bases as an acid dissociation constant, K a:For acids:For bases:K a = (H+ )(A − )(HA)K a = (H+ )(B)(HB + )