1 TOXICOKINETICS Assoc. Prof. PharmDr. Peter Kollár, Ph.D. Department of Pharmacology and Toxicology Faculty of Pharmacy MU Paracelsus (1493 – 1541) ̶ „All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy.“ There are not harmless substances, only a harmless ways of their using. Toxicokinetics ̶ Mathematical modeling of the temporal changes in concentration of xenobiotics that occurs during deposition, absorption, distribution, metabolism, and excretion Toxicokinetics ̶ helps to predict the highest concentrations of xenobiotics, which may occur in organism ̶ helps to predict the time when the concentration of xenobiotics in the organism is close to Ø Toxicokinetic methods ̶ 2 approaches: ̶ Compartment model does not consider anatomy or physiology ̶ Use physiological based toxicokinetic modeling considers physiology and rate limiting biotransformation pathways Mathematical Modeling Classical Method ̶ Plot concentration in blood or tissue with time ̶ Rate of xenobiotic disappearance is proportional to the concentration of xenobiotic in blood or tissue 1st order kinetics ̶ Rate of xenobiotic disappearance is independent of the concentration of xenobiotic in blood or tissue Ø order kinetics 1 and 2 compartment models Physiology-based toxicokinetics ̶ Rate constants for movement of xenobiotic(s) between the various compartments have been measured ̶ Model structure has been derived and tested Example of physiology-based model for inhaled volatile substance ̶ Use rate limiting elimination steps in the model ̶ Applications are species specific Physiology-based toxicokinetics ̶ eg.: cycasin – naturally occuring alkaloid (methylazoxymethanol glycoside) Cycas revoluta Physiology influences toxicity ̶ Bacterial hydrolysis converts cycasin into the strong carcinogen (methylazoxymethanol) ̶ Absolute toxic value for substances does not exist, however, some compounds have much higher relative toxicity than others 1. Relationship between the substance, dose and toxic effect ̶ Toxicity of substances is based on the dose-response relationship ̶ From the dose-response curve values could be derived: ED50, TD50, LD50 and therapeutic index (TI): TI = TD50 / ED50 or TI = LD50 / ED50 ̶ The route of toxic substance entry into the body affects final toxicity ̶ Toxic effect could be as follows: • Immediate or delayed • Direct or indirect • Local or systemic • Reversible or non-reversible ̶ Mixture of toxic compounds could lead to: • Toxic eff. equals the sum of individual components (addition) • Toxic effect higher than the sum (potentiation, synergy) • Different from the individual components of the mixture ̶ Repeated exposure to toxic substance can reduce the toxic effect (tolerance) ̶ appear on the level of: absorption distribution metabolism excretion 2. Factors influencing the toxic response Absorption ̶ is essential for the induction of systemic toxic effects of substances ̶ depends on: • phys.-chem. characteristics of compound (size, structure, solubility, polarity) • way of transport (diffusion, endocytosis, active / passive) • absorption site (skin, GIT, lungs) ̶ Skin • Large surface area • Weak blood flow • hardly permeable ̶ Gastrointestinal tract (GIT) • Main site for absorption • Good blood flow • Large surface area • Various pH • Intestinal bacteria • Various transport processes • Effect of food ̶ Lungs • Huge surface area (50-100 m2) • Well supplied with blood • Easily permeable Distribution ̶ Limited by binding substance on the blood protein • bonds - ionic, hydrophobic, oxygen, Van der Waals (lipophilic DDT binds to the hydrophobic proteins - lipoproteins) ̶ Consequences: • saturation • competitive inhibition • displacement ̶ SATURATION – at higher doses, limited number of specif. binding sites leads to saturation and subsequent release of toxic substances from binding TOXIC THRESHOLD ̶ DISPLACEMENT – between 2 foreign substances – between foreign and endogenous substance TOXIC EFFECT Eg.: sulfisoxazol in preterm infants displace bilirubin from its binding to plasma proteins toxic levels of bilirubin enter the brain Excretion ̶ Rapid excretion decreases the probability of toxic effects and duration of action ̶ It may goes through: • kidney (solid and non-volatile substances) • liver by bile (large polar and amphiphilic substances) • lungs by exspiration (volatile and gaseous substances) • secretion into GIT, milk, saliva, sweat, tears, semen ̶ Biotransformation increases the polarity, size, and MW increased excretion ̶ Biotransformation may lead to toxic substances from less-or non-toxic compounds 3. Factors influencing the toxic response: metabolism ̶ Physico-chemical factors • lipophility • size • polarity pKa • chirality (Eg.: benzopyrene – is metabolized to the trans-epoxide, which is more mutagenic than other enantiomers) 4. Factors affecting the distribution and MTB of toxic substances ̶ Biological factors • gender (parathion is 2x more toxic in F than in M) • genetic factors (idiosyncrasies, polymorphisms) • diet • age (higher permeability of BBB in newborns – neurotoxicity of morphine, Pb) • disease • dose • tissue specificity (uptake by organs such as thyroid gland or lungs – paraquat) • enzymatic induction and inhibition ̶ Direct toxic reactions: tissue damage ̶ Pharmacological, physiological or biochemical effects ̶ Teratogenity ̶ Immunotoxicity ̶ Mutagenity ̶ Carcinogenity Reaction could be as follows: - all-or-none type (death, presence / absence of damage) - graded (biochemical / physiological changes) 5. Reaction of organism to toxic substances Same teratogen administered at different times has different toxicity 36 Thank you for your attention Copyright notice • This material is copyrighted work created by employees of Masaryk university. • Students are allowed to make copies for learning purposes only. • Any unauthorised reproduction or distribution of this material or its part is against the law.