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Pharmacocinétique Suite: Métabolisme Et Élimination Rénale

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Pharmacocinétique Suite: Métabolisme Et Élimination Rénale PHARMACOKINETIC Drug-Drug Interactions : consequence of binding-unbinding plasma protein on distribution volume. 2 Factors modifying VD Obese patients : increase VD for very lipophilic drugs: Diazepam, Thiopental Hydro-electrolytic disturbances, elderly patients Modifications of natural barriers : placenta, blood-brain barrier 3 Natural Barrier 4 Blood-Brain Barrier 5 Distribution in the CNS The brain capillary membrane is lined with a fabric of glial astrocytes support, thus creating a double barrier - glial membrane and capillary endothelium – very few hydrophilic molecules can cross BBB. The cerebral capillaries are formed of closely contiguous endothelial cells, devoid of intercellular pores and fully covered with cellular elements, mainly of astrocytes. The transcellular penetration appears to be the most plausible The flow of cerebrospinal fluid is the only limiting factor for the diffusion of lipophilic molecule 6 Placenta barrier Placenta = organ of exchange of substances between mother and fetus. The placental diffusion is from the mother to the embryo through the placental barrier. The soluble and non-ionized molecules easily cross the barriers encountered three, namely: The trophoblastic epithelium, The mesenchymal tissue and The vascular endothelium 7 Fetal compartment 4 compartments: 1. Fetal blood 2. Extravascular fluid 3. Umbilical cord 4. Amniotic fluid. 8 Mechanism involved The mechanism of exchange through the placenta is essentially a process of passive diffusion. Active transport and facilitated diffusion exist for endogenous substances but not to exogenous substances. The Fick's law applies also in this case: Diffusion rate = DKsS (Cm-Cf) / E D: diffusion constant S: exchange surface Ks: Partition coefficient between the placental barrier and the external phase Cm - Cf: concentration difference between the mother and the fetus. E: Thickness The drug is then distributed to the fetus. The affinity of the drug for fetal tissue is often the same as the mother in late pregnancy but it is different in the first month of pregnancy. After metabolism, metabolites return to the mother through the umbilical arteries 9 Drugs in lactation Questions: 1. Does the drug taken by the mother passes into breast milk? 2. In what concentration (we found it in children)? 3. What is the amount of milk drunk? (150ml/kg/day) Incomplete responses for most drugs! 10 Références Drugs in Pregnancy and Lactation, 9th Edition G.G. Briggs, R.K. Freeman, and S.J. Yaffe Lippincott Williams & Wilkins 11 Metabolism and renal elimination Clearance The concept of clearance (English word) was introduced in 1973 by Rowland in pharmacokinetics, it is used to describe the removal of a substance: either by whole body (total body clearance) or by cleansing organs (renal clearance, hepatic, ...). These different mechanisms of elimination are additive (additive clearances), they contribute to the elimination from the body (total clearance). 13 Clairance: additive Cl totale = Cl hépatique + Cl rénale + …. = ΣCl partielles 14 Equation The clearance (CL) indicates the ability of an organ to completely purify a volume of fluid per unit of time. The clearance unit is generally l.h-1 or ml min-1. There are different clearances (according to the purified fluid, or organ so the mechanisms involved are multiple). Its value can not exceed the maximum value of the flow : E = 1 Cl=Q 15 Concepts et définitions Q = Blood flow in the organe Ca = concentration afférente (artérielle) Cv = concentration efférente (veineuse) 16 Metabolism Metabolism is a part of the elimination process of a drug. The metabolism of a drug corresponds to the transformation by an enzymatic reaction of a drug to one or or more compounds, said metabolites. Metabolites may be pharmacologically inactive or pharmacologically sometimes toxic. Hydroxylation is the most frequent biotransformation. 17 General Metabolic Pathways Oxidation Hydrolytic Reactions Aromatic moieties Esters and amides Olefins Epoxides and arene oxides Benzylic & allylic C atoms by epoxide hydrase and a-C of C=O and C=N At aliphatic and alicyclic C C-Heteroatom system Phase II - Phase I - C-N (N-dealkylation, N-oxide Conjugation formation, N-hydroxylation) Functionalization C-O (O-dealkylation) C-S (S-dealkylation, S-oxidation, desulfuration) Drug Oxidation of alcohols and Metabolism aldehydes Miscellaneous Reduction Glucuronic acid conjugation Aldehydes and ketones Sulfate Conjugation Nitro and azo Glycine and other AA Miscellaneous Glutathion or mercapturic acid Acetylation Methylation 18 Métabolisme (2) Phase I Phase II Introduction ou exposition Réactions de conjugaison d’un groupe réactif hydrosolubilité The result is the production of a conjugated derivative highly hydrosoluble (more polar) which makes possible its elimination by the kidney, 19 The aim of the metabolism step 20 Active/inactive metabolite It is important to note that drug metabolism does not necessarily lead to its inactivation. Thus, prodrugs (or pro-drugs) are pharmacologically inactive, they are rapidly metabolized to the pharmacologically active metabolites. 21 Metabolite Examples and notes activity Inactive Routes that result in the formation of inactive metabolites are often referred to as detoxification. (detoxification) OH O O Phenol sulphokinase S O OH 3'-Phosphoadenosine-5'- Phenol phosphosulfate (PAPS) Phenyl hydrogen sulfate Similar activity The metabolite may exhibit either a different potency or duration of action or both to the original drug. CH3 CH to the drug O 3 O H O N N N Hydroxylation N-Demethylation OH OH Cl N Cl N Cl N Ph Ph Ph Diazepam Temazepam Oxazepam (Sustained anxiolytic action) (Short duration) (short duration) CH3 CONHNHCH CONHNH2 Different CH3 N-Dealkylation activity N N Ipronazid Isoniazid (Antidepressant) (Antituberculosis) HO NCOCH3 NHCOCH3 NH2 Other substances responsible for Substances responsible Toxic hepatotoxicity for methemoglobinamia metabolites OC2H5 OC2H5 OC2H5 N-Hydroxyphenacetin Phenacetin Phenetidine (Hepatotoxic) (Analgesic) 22 Enzymes Involved in Drug Metabolism CYP450, Hepatic microsomal flavin containing monooxygenases (MFMO or FMO) Monoamine Oxidase (MAO) and Hydrolases Cytochrome P450 system: localized in the smooth endoplasmic reticulum. Simplified apoprotein portion Cytochrome P450 is a Pigment that, with CO bound to the reduced form, absorbs maximally at 450nm L CH3 CH3 HOOC Cytochromes are hemoproteins (heme-thiolate) that N N CH2 function to pass electrons by reversibly changing the Fe+3 oxidation state of the Fe in heme between the 2+ and 3+ N N CH3 state and serves as an electron acceptor–donor HOOC CH3 CH2 P450 is not a singular hemoprotein but rather a family O of related hemoproteins. Over 1000 have been H R identified in nature with ~50 functionally active in Substrate binding site humans with broad substrate specificity Heme portion with activated Oxygen 23 Cytochrome P450: Naming ■ Before we had a thorough understanding of this enzyme system, the CYP450 enzymes were named based on their catalytic activity toward a specific substrate, e.g., aminopyrine N-demethylase now known as CYP2E1 ■ Currently, all P450’s are named by starting with “CYP” (CYtochrome P450, N1, L, N2 - the first number is the family (>40% homology), the letter is the subfamily (> 55% homology), and the second number is the isoform. The majority of drug metabolism is by ~10 isoforms of the CYP1, CYP2 and CYP3 families in humans ■ Major human forms of P450: Quantitatively, in the liver the percentages of total P450 protein are: CYP3A4 – 28%, CYP2Cx – 20%, CYP1A2 – 12%, CYP2E1 – 6%, CYP2A6 – 4%, CYP2D6 – 4% ■ By number of drugs metabolized the percentages are: CYP3A4 – 35%, CYP2D6 – 20%, CYP2C8 and CYP2C9 – 17%, CYP2C18 and CYP2C19 - 8% CYP 1A1 and CYP1A2 -10%, CYP2E1 – 4%, CYP2B6 – 3% 24 Few Important CYP450 Isozymes CYP Main functions family CYP1 Xenobiotic metabolism CYP2 Xenobiotic metabolism, Arachidonic acid metabolism CYP3 Xenobiotic and steroid metabolism CYP7 Cholesterol 7α-hydroxylation CYP11 Cholesterol side-chain cleavage, Steroid 11β – hydroxylation, Aldosterone synthesis CYP17 Steroid 17α-hydroxylation CYP19 Androgen aromatization CYP21 Steroid 21-hydroxylation CYP24 Steroid 24-hydroxylation CYP27 Steroid 27-hydroxylation 25 EC Recommended name Family/gene 1.3.3.9 * secologanin synthase CYP72A1 1.14.13.11 * trans-cinnamate 4-monooxygenase CYP73 1.14.13.12 * benzoate 4-monooxygenase CYP53 1.14.13.13 * calcidiol 1-monooxygenase CYP27 1.14.13.15 * cholestanetriol 26-monooxygenase CYP27 1.14.13.17 * -monooxygenase CYP7 1.14.13.21 * flavonoid 3'-monooxygenase CYP75 1.14.13.28 * 3,9-dihydroxypterocarpan 6a-monooxygenase CYP93A1 1.14.13.30 * leukotriene-B4 20-monooxygenase CYP4F 1.14.13.37 * methyltetrahydroprotoberberine 14-monooxygenase CYP93A1 1.14.13.41 * tyrosine N-monooxygenase CYP79 26 Drug Interactions & Metabolism The drug interactions depend upon: a) the isoform(s) required by the drug in question, b) the isoforms altered by concomitant therapy, c) the type of enzyme alteration (induction or inhibition). 27 General Metabolic Pathways Oxidation Hydrolytic Reactions Aromatic moieties Esters and amides Olefins Epoxides and arene oxides Benzylic & allylic C atoms by epoxide hydrase and a-C of C=O and C=N At aliphatic and alicyclic C C-Heteroatom system C-N (N-dealkylation, N-oxide Phase II - Phase I - formation, N-hydroxylation) Conjugation C-O (O-dealkylation) Functionalization C-S (S-dealkylation, S-oxidation, desulfuration) Oxidation of alcohols and Drug aldehydes Metabolism
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