Biochemistry - Distribution Renal Elimination

Drug distribution: Compartments Interstitial volume (15% body weight)Intravascular volume(5% body weight)Intracellular volume(40% body weight)Body fat (several % body weight)Factors affecting the equilibrium distribution of drugs across the compartments1.Membrane-impermeant drugs will be excluded from the intracellular volume (Example: Lithium)2.Lipophilic drugs will be enriched in the fat tissue (example: Thiopental –see later)3.Drugs with a high degree of protein binding will be more concentrated in the plasma (the intravascular volume) than in the interstitial fluid The ‘volume of distribution’Vd =Amount of drug in the body Drug plasma concentrationLipophilic drugs: Vd> total body volumeExtracellularly confined drugs: Vd< total body volumeIntravascularly confined drugs: Vd<< total body volumeProtein binding•Protein binding is largely determined by the hydrophobicity of the drug molecule•Main carrier protein in blood plasma is albuminKinetic aspects of drug distribution: Thiopental0204060801000.11101001000BloodBrainLean tissuesFatNHNHSOOCH3CH3CH3Time after intravenous application (min.)Fractionaldistribution (%)Drug elimination (1): KidneyTypical pathways:Hydrophilic drug moleculeKidneyUrineHydrophobic drug moleculeLiverMore hydrophilic metaboliteAnatomy of the kidneys and urine excretion organsKidney function1.Filtration: The kidneys are perfused at a rate of ~1.2 l/min. Approximately 10% of the plasma volume is squeezed across a filtering membrane that retains most macromolecules but lets through small molecules2.Re-absorption: Most small solutes –glucose, salts, amino acids –are taken up again by specific transporters. Wateris recovered by the ensuing osmotic effect. Somesolutes are partially or totally excluded from reuptake3.Some substrates are actively secreted from the blood into the nascent urineUrine is ‘distilled’ from blood plasma in several stages:Kidney structure: Glomerulus and tubuliThe nephronThe nephronReuptakeSecretionFiltrationPrimary filtration in the glomerulus (1) afferent arterioleefferent arterioleproximal tubuleBowman’s capsulePrimary filtration in the glomerulus (2) Basal membraneEndothelial cell withfenestrationsPodocyte pseudopodiaFiltration slitsBloodPrimary filtrateSegments of the nephronproximal straighttubuleproximal convoluted tubuledistal convoluted tubulecollectingductthin descending limbLoop ofHenlethin ascending limbSegments of the nephron and their functionsReuptake ofglucose, amino acids, bicarbonate, …Active secretion of uric acid, organic acids, organic bases Reuptake ofsalts and waterFiltrationReuptake of weak organicacids and bases Excretion of membrane-permeant versus non-permeant molecules (1)n=constantc=constantFlow along tubuleResidual volumepermeantnon-permeantExcretion of membrane-permeant versus non-permeant molecules (2)ConcentrationsFractions retained in filtrateimpermeantpermeantTraveled tubule lengthForced diuresis for accelerated elimination of poisonsFlow along tubulePrimary filtration in the glomerulus (2) Basal membraneEndothelial cell withfenestrationsPodocyte pseudopodiaFiltration slitsBloodPrimary filtrateThe volume flow rate of glomerular filtration•The glomerular filtration rate is the major determinant in the rate of excretion of polar solutes•The glomerular filtration rate shows substantial variation with age and can be substantially reduced in patients with prior kidney diseaseWe need to measure itMeasurement of the glomerular filtration rate using the inulin ‘clearance’GFR = Inuline clearance = Urine flow rate Urine concentrationFiltrate concentrationPlasma concentration= filtrate concentrationUrine concentration, flow rateActive secretion of p-aminohippurate in the proximal tubuleTissueTubule+++---+++p-AH-a-Ketoglutarate--,other divalent anionsNH2ONHCH2OOp-AH-Cl-, HCO3-,…p-AHp-Aminohippurate clearance measures renal plasma flowUrine flow rate Urine concentrationFiltrate concentrationRenal plasma flow = pAH clearance =Probenecid inhibits tubular secretion of penicillinpenicillina-Ketoglutarate--penicillinCl-, HCO3-,…probenecidNSOOC3H7C3H7OONSNHOCH2OCH3CH3COOpenicillin GprobenecidThe extent of a drug’s reuptake in the distal tubule depends on its membrane permeabilityNHNCH2SCH2CH2NHCNNHCH3CH3CNProtein-bound (%)CimetidineNHNHOOOC2H5PhenobarbitalClearance (L/h)Half-life (h)Cimetidine19322Phenobarbital510.2598Drug reuptake may vary with urine pH: LSD as an exampleNHNCONNH2+NH+CONNeutral or alkaline pHAcidic pH