Bioavailability of drgs that follow nonlinear pharmacokinetics

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2. CONTENTS: INTRODUCTION BIOAVAILABILITY OF DRUGS THAT FOLLOW NON-LINEARPHARMACOKINETICS DEFINITION OF CHRONOPHARMACOKINETICS BODYRHYTHMS DESIGN OF A CHRONOPHARMACOKINETIC STUDY CIRCADIAN DEPENDENCE OF DRUGPHARMACOKINETICS CONCLUSION REFERENCE 3. INTRODUCTION:In some instances,the rate process of adrugs ADME are dependent upon carrier or enzymes that aresubstrate specific,have definite capacities,and susceptible to saturationat high drug concentration.In such cases,an essentially first order kinetics transform into amixture of first order and zero order rate processes and thepharmacokinetic parameters change with the size of the administereddose.The pharmacokinetics of such drugs are said to be dose-dependent.Other terms synonymous with it are mixed-order,nonlinearand capacity-limited kinetics. 4. BIOAVAILABILITY OF DRUGS THAT FOLLOWNONLINEAR PHARMACOKINETICS:The bioavailability of drugs that follow nonlinearpharmacokinetics is difficult to estimate accurately. Each process of drug absorption, distribution, andelimination is potentially saturable. Drugs that follow linear pharmacokinetics follow the principleof superposition . The assumption in applying the rule ofsuperposition is that each dose of drug superimposes on theprevious dose 5. An example of a drug with dose-dependent absorption ischlorothiazide. The extent of bioavailability is generally estimated using [AUC]. If drug absorption is saturation limited in the gastrointestinaltract, then a smaller fraction of drug is absorbed systemicallywhen the gastrointestinal drug concentration is high. A drug with a saturable elimination pathway may also have aconcentration dependent AUC affected by the magnitude of Kmand V max of the enzymes involved in drug elimination . 6. At low Cp, the rate of elimination is first order, even at thebeginning of drug absorption from the gastrointestinal tract.As more drug is absorbed, either from a single dose or aftermultiple doses, systemic drug concentrations increase to levelsthat saturate the enzymes involved in drug elimination.Drug concentrations increase to levels that saturate theenzymes involved in drug elimination. The body drug clearance changes and the AUC increasesdisproportionately to the increase in dose. 7. CHRONOPHARMACOKINETICS: Chronopharmacokinetics decribe the changes indrug absorption,distribution,metabolism and orelimination due to normal physiological circadianrhythms. 8. BODY RHYTHMS These are the biological process that show cyclicvariation over time.TYPES OF BODY RHYTHMS CIRCADIAN RHYTHMSwhich lasts for about one day,like-sleep walking rhythm-the body temperature 9. ULTRADIAN RHYTHMSshorter that a day,few seconds like-heart beatINFRADIAN RHYTHMSlonger than a day,like-monthly rhythm-menstrual cycle-yearly rhythm bird migration 10. CIRCADIAN CLOCK SHOWING EFFECTS OFBODY RHYTHMS ON PHYSIOLOGICALPROCESSES. 11. DESIGN OF ACHRONOPHARMACOKINETIC STUDYIn a chronopharmacokinetic study many factors of variation mustbe controlled : factors related to drug itself:influence of food,galenic formulation,drug interactions subject related factors:age,gender,pathology,posture,exercise factors related to conditions of administration:single or repeated dosingconstant rate deliveryroute of administration 12. There are some instances in which achronopharmaco- kinetic study is needed: When possible daily variations inpharmacokinetics may be responsible for timedependent variations in drug effects. When drugs have a narrow therapeutic index When symptoms of a disease are clearlycircadian phase dependent e.g.(nocturnal asthma,angina pectoris,myocardial infarction,ulcer.) 13. CIRCADIAN DEPENDENCE OF DRUGPHARMACOKINETICSABSORPTIONis altered by circadian (rhythms) likechanges in -gastric emptying time-GI blood flow-gastric acid secretion and pH.most LIPOPHILIC drugs seems to be absorbed fasterwhen the drug is taken in the MORNING compared withthe evening.e.g: absorption of VALPROIC ACID larger in themorning than in the evening. 14. Absorption by other routes of administration may alsobe influenced by biological rhythms.For instance,in children,the skin penetration of aneutectic mixture of lidocaine and prilocaine was reportedto depend on the time of aministration,with a higher rateof penetration occuring in the evening.In addition,circadian dose administrationtimedependency in the forearm skin penetration ofhydrophillic methylnicotinate and lipophillichexylnicotinate was recently demonstrated.Circadian variations have also beeen reported in theoccular absorption of topically applied timolol. 15. DISTRIBUTIONIt is altered by circadian changes in-bodysize and composition-blood flow to various organs-drug protein binding.Peak plasma concentration of plasma proteins likealbumin occurs early in the afternoon,while troughs arefound during the night. circadian variations in the drug protein binding ofacidic and basic drugs have been reported both inhumans and animal studies.e.g: free plasma concentrations for anticonvulsant drugssuch as carbamazepine,diazepam,phenytoin and valproicacid,and for antineoplastic drugs such as cisplatin have 16. been documented,these changes are usually reported to bedependent on temporal variations in plasma proteinlevels,which are circadian-time dependent.The time dependency of the passage of drugs into redblood cells also provides a strong argument for theexistence of temporal variations in the passage of drugsthrough biological membranes,for which red blood cellsare often used as a model. 17. METABOLISMHepatic drug metabolism is generally assumed todepend on liver enzyme activity and orhepatic blood flow.Both have been shown to be circadian time-dependent.Circadian variations in enzyme activity weredocumented in the liver,kidney and brain,however thesedata were obtained in animals and no direct data onenzyme activity have been reported in humans. For drugs with a high extraction ratio,hepaticmetabolism depends on hepatic blood flow. 18. several experimental and clinical pharmacologicalstudies have indirectly investigated temporal variationsin hepatic drug metabolism capacity by evaluating thechronokinetics of drugs and their metabolites,even if notpharmacologycally active.Thus conjugation,hydrolysis,and oxidation were shownto be circadian timedependent.As far as metabolic phenotype is concerned,the effectof diurnal variation on debrisoquine metabolicphenotyping,with the slowest rate of metabolismoccuring dring the day time. 19. ELIMINATIONMost drugs are eliminated via the kidneys.Glomerular filtration,Renal blood flow,Urinary pH andTubular resorptionhave all been shown to be circadian timedependent,with higher values during the day time inhumans.Thus,the urinary excretion of many drugs maydepend on these rhythmic variations. 20. Renal elimination depends partially on theionisation of drugs,and thus may be modified bytemporal changes in urinary pH.This has been described for acidic drugs such assodium salicylate and sulfasymazine,which are excretedmore quickly after evening than morningadministration. 21. CONCLUSION Chronopharmacokinetics is a successful toolin the hands of clinical pharmacist ,which ifjudiciously exploited can help in bettertherapeutic drug monitoring,thus reducing sideeffects and providing better patient care. 22. REFERENCE Biopharmaceutics and pharmacokinetics byD.M.Brahmankar and Sunil B.Jaiswal,pageno(273). Biopharmaceutics and pharmacokinetics Secondedition by V.Venkateshwarlu,page no(355-360). Applied Biopharmaceutics andPharmacokinetics,fifth edition by LeonShargel,page no(295-299). International Journal of Pharmacy andPharmaceutical sciences,vol-4,Issue4,2012,Review Article.