A Practical Approach, Second Edition=Ronald D. Ho.pdf

USE OF TOXICOKINETICS IN DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY 573a complex that diffuses across membranes, depending on the concentration gradient. Active transportis a cellular-energy requiring process for movement of molecules against a concentration gradient.Several essential nutrients (e.g., amino acids, calcium, vitamin B 12 ) cross the placenta by activetransport. 2 Xenobiotics may also be subject to carrier-mediated transport. The p-glycoproteins (alsoknown as multidrug-resistant [mdr] proteins), organic-anion transporters, and organic-cation transporterscan actively “pump” certain xenobiotics out of cells. Gastrointestinal absorption of severaldrugs is limited by mdr activity in intestinal enterocytes. 3 Placental mdr has been shown to modulatethe teratogenic potential of avermectin, as mdr null-mutant mice are more susceptible to theinduction of cleft palate by that drug. 4 Macromolecules can move across cellular membranes bycellular pinocytosis (engulfing of fluid) or endocytosis (receptor mediated internalization, e.g.,movement of iron-transferrin across hemochorial placentas). 2When movement of a substance (e.g., anesthetic gases such as nitrous oxide or halothane 1 )across cell membranes is very rapid relative to the rate of blood flow to the tissue, uptake into thattissue is termed “flow-limited.” Conversely, when uptake is rate limited by movement across cellmembranes (e.g., antibiotics such as penicillin or streptomycin 5 ), uptake is considered to be “membranelimited” (or “diffusion limited” when that movement occurs by passive diffusion).B. Plasma Protein BindingThe binding of a xenobiotic to blood plasma proteins can be an important determinant of itsdistribution and elimination. Many drugs noncovalently bind to albumins, globulins, or lipoproteins.5 The large molecular radius of the drug-protein complex can effectively retard passivediffusion across membranes and thereby limit drug distribution into tissues and limit glomerularfiltration, both of which can influence toxicity. The extent of plasma protein binding by a compoundcan be assessed by ultrafiltration or equilibrium dialysis and is commonly expressed as %fu, thefraction of drug unbound by plasma protein, i.e., the “free fraction.” It is not uncommon for thereto be species differences in %fu, and small differences can be important. For example, considerthe case of a drug with %fu = 0.5% (99.5% bound) in the rat and %fu = 1.5% (98.5% bound) inhumans. At the same total concentration in plasma, the “free” drug concentration, which is freelydiffusible across cellular membranes into target organs, is three times higher in humans than inrats. Such a difference could be associated with a greater potential for toxicity. At the same time,urinary excretion of the drug could be greater in humans and might lower the potential for toxicity.It should also be appreciated that %fu can vary according to total drug concentration, given a finitenumber of binding sites on plasma protein. 5Unexpected drug interactions can occur when there is competition for binding to plasmaproteins. If a drug with a low %fu, such as digitoxin (%fu = 2%), is only 10% displaced fromplasma protein binding, the “free” drug concentration increases sixfold (%fu increases from 2% to12%). 6 Such interactions can have adverse consequences. An example is kernicterus in infantsresulting from displacement of bilirubin from plasma proteins by sulfonamide drugs, which competefor the bilirubin binding site, leading to more “free” bilirubin diffusion into the brain. 6C. Volume of DistributionAn empirical indication of how extensively a xenobiotic is distributed throughout the body is givenby the apparent volume of distribution (V d ), the virtual fluid volume in which the total amount ofdrug in the body appears to be dissolved to account for the measured drug concentration. Conceptually,a drug restricted to blood plasma (and assuming that the drug is not bound, metabolized, oreliminated) has a V d equivalent to the total blood plasma volume (about 3 liters for a 70-kg human);a drug widely distributed throughout all intracellular and extracellular (interstitial) space has a V dequivalent to the total body water volume (about 41 liters). The V d can be determined experimentallyby giving the test article as a bolus intravenous dose, in which case:© 2006 by Taylor & Francis Group, LLC