Pharmacokinetics PDF

PH A RMA CO K INET ICS DR. DANTE ESTANDARTE  PHARMACOKINETICS is currently defined as the study of the time course of drug absorption, distribution, metabolism, and excretion DEFINITION CLINICAL...

PH A RMA CO K INET ICS DR. DANTE ESTANDARTE  PHARMACOKINETICS is currently defined as the study of the time course of drug absorption, distribution, metabolism, and excretion DEFINITION CLINICAL PHARMACOKINETICS is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient REVIEW STRUCTURE OF PLASMA MEMBRANE CONSISTS OF A BILAYER OF AMPHIPATHIC (HAVING BOTH HYDROPHILIC AND HYDROPHOBIC PARTS) LIPIDS HYDROCARBON CHAINS ORIENTED INWARD TO THE CENTER OF THE BILAYER TO FORM A CONTINUOUS HYDROPHOBIC PHASE HYDROPHILIC HEADS ORIENTED OUTWARD CHARACTERISTICS OF PLASMA MEMBRANE LIPID MOLECULES IN THE BILAYER ENDOW THE MEMBRANE WITH FLUIDITY PROPERTY BY VIRTUE OF WHICH, THE PARTICLES OF A MOLECULE MOVE IN SPACE. FLEXIBILITY, ORGANIZATION, HIGH ELECTRICAL RESISTANCE, AND RELATIVE IMPERMEABILITY TO HIGHLY POLAR MOLECULES  MEMBRANE PROTEINS MEMBRANE PROTEINS INTEGRAL MEMBRANE PROTEINS THAT ARE PERMANENTLY ANCHORED OR PART OF THE MEMBRANE PERIPHERAL MEMBRANE PROTEINS THAT ARE ONLY TEMPORARILY ATTACHED TO THE LIPID BILAYER OR TO OTHER INTEGRAL PROTEINS  MEMBRANE PROTEINS EMBEDDED IN THE BILAYER SERVE AS STRUCTURAL ANCHORS, RECEPTORS, ION CHANNELS, AQUEOUS PORES, TRANSPORTERS  CELL MEMBRANES ARE RELATIVELY PERMEABLE TO WATER BY FLOW RESULTING FROM HYDROSTATIC OR OSMOTIC DIFFERENCES ACROSS THE MEMBRANE BULK FLOW OF WATER CAN CARRY WITH IT SMALL WATER-SOLUBLE SUBSTANCES PROTEINS WITH DRUG MOLECULES BOUND TO THEM ARE TOO LARGE AND POLAR FOR MEMBRANE PASSAGE TO OCCUR. TRANSMEMBRANE MOVEMENT OF DRUG GENERALLY IS LIMITED TO UNBOUND DRUG. DRUG-PROTEIN COMPLEXES CONSTITUTE AN INACTIVE RESERVOIR OF DRUG THAT CAN INFLUENCE BOTH THERAPEUTIC AS WELL AS UNWANTED DRUG EFFECTS MOSTLIPOPHILIC DRUGS CAN PASS THROUGH THE CELL MEMBRANE ITSELF  DIFFUSION IS THE MOVEMENT OF A SUBSTANCE FROM AN AREA OF HIGH CONCENTRATION TO AN AREA OF LOW CONCENTRATION. OSMOSISIS A PROCESS BY WHICH MOLECULES OF A SOLVENT TEND TO PASS THROUGH A SEMIPERMEABLE MEMBRANE FROM A LESS CONCENTRATED SOLUTION INTO A MORE CONCENTRATED ONE, THUS EQUALIZING THE CONCENTRATIONS ON EACH SIDE OF THE MEMBRANE. FACTORS AFFECTING TRANSFER OF DRUGS ACROSS MEMBRANES MOLECULAR SIZE DEGREE OF IONIZATION (POLARITY, AQUEOUS SOLUBILITY) LIPID SOLUBILITY BINDING TO TISSUE AND SERUM PROTEINS BOUND DRUG DOES NOT CONTRIBUTE DIRECTLY TO THE CONCENTRATION GRADIENT THAT DRIVES DIFFUSION PROTEINS WITH DRUG MOLECULES BOUND TO THEM ARE TOO LARGE AND POLAR CONCENTRATION GRADIENT SURFACE AREA THICKNESS OF THE BARRIER MEMBRANE ACID – PROTON DONOR BASE – PROTON ACCEPTOR MECHANISMS BY WHICH DRUGS CROSS MEMBRANES/ ACROSS COMPARTMENTS PASSIVE TRANSPORT (NO ENERGY) PARACELLULAR TRANSPORT - THROUGH INTERCELLULAR GAPS IN SOME ORGANS, ESPECIALLY THE CENTRAL NERVOUS SYSTEM (CNS) AND THE PLACENTA, THERE ARE TIGHT JUNCTIONS BETWEEN THE CELLS  SIMPLE DIFFUSION THROUGH AQUEOUS PORES FORMED BY SPECIAL PROTEINS (AQUAPORINS) THAT TRAVERSE THE LIPID ABSENT IN BRAIN  DIFFUSION DIRECTLY THROUGH THE LIPID DIFFUSION INFLUENCED BY POLARITY - MAIN LIPID SOLUBILITY – MAIN MOLECULAR SIZE (THE SMALLER THE MOLECULE, THE FASTER THE RATE) MAGNITUDE OF CONCENTRATION GRADIENT ACROSS THE MEMBRANE PH PARTITION PH PARTITION IS THE TENDENCY FOR ACIDS TO ACCUMULATE IN BASIC FLUID COMPARTMENTS, AND BASES TO ACCUMULATE IN ACIDIC COMPARTMENTS. E.G., ALKALINE URINE FAVORS EXCRETION OF WEAK ACIDS; ACID URINE FAVORS EXCRETION OF WEAK BASES. ELEVATION OF URINE PH (BY GIVING SODIUM BICARBONATE) WILL PROMOTE URINARY EXCRETION OF WEAK ACIDS SUCH AS URIC ACID ION TRAPPING = IONIZED DRUG TRAP GETS TRAPPED ON ONE SIDE OF A MEMBRANE THAT DIVIDES COMPARTMENT WITH DIFFERENT PH ION TRAPPING ACIDS BECOME NEGATIVELY ELECTRIC CHARGED IN BASIC FLUIDS, SINCE THEY DONATE A PROTON. BASES BECOME POSITIVELY ELECTRIC CHARGED IN ACID FLUIDS, SINCE THEY RECEIVE A PROTON. SINCE ELECTRIC CHARGE DECREASES THE MEMBRANE PERMEABILITY OF SUBSTANCES, ONCE AN ACID ENTERS A BASIC FLUID AND BECOMES ELECTRICALLY CHARGED, THEN IT CANNOT ESCAPE THAT COMPARTMENT WITH EASE AND THEREFORE ACCUMULATES; AND VICE VERSA WITH BASES.  MEMBRANE SURFACE AREA EXPOSED TO THE DRUG PROTEIN BINDING PROTEINS ARE LARGE MOLECULES PLASMA ALBUMIN IS MOST IMPORTANT PLASMA ALBUMIN BINDS MAINLY ACIDIC DRUGS; Β- GLOBULIN AND ACID GLYCOPROTEIN ALSO BIND SOME BASIC DRUGS IT IS THE UNBOUND DRUG THAT IS PHARMACOLOGICALLY ACTIVE  UNBOUND DRUG: PASSES THROUGH MEMBRANE THEREFORE IMPORTANT IN DISTRIBUTION CONTRIBUTES TO CONCENTRATION THEREFORE IMPORTANT IN CONCENTRATION GRADIENT REACHES TARGET SITES THEREFORE PHARMACOLOGICALLY ACTIVE BOUND DRUG SERVES AS DRUG RESERVOIR CARRIER-MEDIATED MEMBRANE TRANSPORT FACILITATED DIFFUSION ALSO KNOWN AS FACILITATED TRANSPORT OR PASSIVE- MEDIATED TRANSPORT VIA SPECIFIC TRANS MEMBRANE INTEGRAL PROTEINS – DIFFERENT FROM SIMPLE DIFFUSION THERE IS NO INPUT OF ENERGY, AND THEREFORE ENHANCED MOVEMENT OF THE INVOLVED SUBSTANCE IS DOWN A CHEMICAL GRADIENT CAPACITY-LIMITED ACTIVE TRANSPORT CHARACTERIZED BY A DIRECT REQUIREMENT FOR ENERGY MOVEMENT AGAINST AN ELECTROCHEMICAL GRADIENT CAPACITY-LIMITED ENDOCYTOSIS PERMITSVERY LARGE OR VERY LIPID- INSOLUBLE CHEMICALS TO ENTER CELLS. E.G., PROTEINS, POLAR MOLECULES, LIPID INSOLUBLE MOLECULES PHAGOCYTOSIS PINOCYTOSIS RECEPTOR- MEDIATED ENDOCYTOSIS EXOCYTOSIS PHASES OF PHARMACOKINETICS  MOVEMENT OF A DRUG FROM ITS SITE OF ADMINISTRATION INTO THE CENTRAL COMPARTMENT (CIRCULATION) ABSORPTIO FOR SOLID DOSAGE N OF DRUGS FORMS, ABSORPTION FIRST REQUIRES DISSOLUTION OF THE TABLET OR CAPSULE, THUS LIBERATING THE DRUG.  PATH BY WHICH A DRUG IS TAKEN INTO THE BODY ROUTES OF DRUG ADMINISTRATION TAKEN BY MOUTH (ORALLY) GIVEN BY INJECTION INTO A VEIN (INTRAVENOUSLY, IV), INTO A MUSCLE (INTRAMUSCULARLY, IM), INTO THE SPACE AROUND THE SPINAL CORD (INTRATHECALLY), OR BENEATH THE SKIN (SUBCUTANEOUSLY, SQ) PLACED UNDER THE TONGUE (SUBLINGUALLY) OR BETWEEN THE GUMS AND CHEEK (BUCCALLY) INSERTED IN THE RECTUM (RECTALLY) OR VAGINA (VAGINALLY) PLACED IN THE EYE (BY THE OCULAR ROUTE) OR THE EAR (BY THE OTIC ROUTE)  SPRAYED INTO THE NOSE AND ABSORBED THROUGH THE NASAL MEMBRANES (NASALLY) BREATHED INTO THE LUNGS, USUALLY THROUGH THE MOUTH (BY INHALATION) OR MOUTH AND NOSE (BY NEBULIZATION) APPLIED TO THE SKIN (CUTANEOUSLY) FOR A LOCAL (TOPICAL) OR BODYWIDE (SYSTEMIC) EFFECT DELIVERED THROUGH THE SKIN BY A PATCH (TRANSDERMALLY) FOR A SYSTEMIC EFFECT ORAL ADMINISTRATION ORAL INGESTION IS THE MOST COMMON METHOD OF DRUG ADMINISTRATION. IT ALSO IS THE SAFEST, MOST CONVENIENT, AND MOST ECONOMICAL. DISADVANTAGES LIMITED ABSORPTION OF SOME DRUGS BECAUSE OF THEIR PHYSICAL CHARACTERISTICS (E.G., LOW WATER SOLUBILITY OR POOR MEMBRANE PERMEABILITY), EMESIS AS A RESULT OF IRRITATION TO THE GI MUCOSA, DESTRUCTION OF SOME DRUGS BY DIGESTIVE ENZYMES OR LOW GASTRIC PH, IRREGULARITIES IN ABSORPTION OR PROPULSION IN THE PRESENCE OF FOOD OR OTHER DRUGS, AND THE NEED FOR COOPERATION ON THE PART OF THE PATIENT DRUGS IN THE GI TRACT MAY BE METABOLIZED BY THE ENZYMES OF THE INTESTINAL FLORA, MUCOSA, OR LIVER BEFORE THEY GAIN ACCESS TO THE GENERAL CIRCULATION (FIRST-PASS EFFECT) ABSORPTION FROM THE GI TRACT IS GOVERNED BY FACTORS PRESENCE OF FOOD SEVERAL DRUGS REACH A HIGHER PLASMA CONCENTRATION IF THEY ARE TAKEN AFTER A MEAL, PROBABLY BECAUSE FOOD INCREASES SPLANCHNIC BLOOD FLOW SURFACE AREA FOR ABSORPTION THE DRUG’S CONCENTRATION AT THE SITE OF ABSORPTION BLOOD FLOW TO THE SITE OF ABSORPTION THE PHYSICAL STATE OF THE DRUG (SOLUTION, SUSPENSION, OR SOLID DOSAGE FORM) WATER SOLUBILITY GASTROINTESTINAL PH PHYSICOCHEMICAL INTERACTION WITH GUT CONTENTS E.G., CHEMICAL INTERACTION BETWEEN CALCIUM AND TETRACYCLINE ANTIBIOTICS FIRST-PASS EFFECT CONTROLLED-RELEASE PREPARATIONS POTENTIAL ADVANTAGES OF SUCH PREPARATIONS ARE REDUCTION IN THE FREQUENCY OF ADMINISTRATION (OFTEN WITH IMPROVED COMPLIANCE BY THE PATIENT) MAINTENANCE OF A THERAPEUTIC EFFECT OVERNIGHT (MOST APPROPRIATE FOR DRUGS WITH SHORT HALF-LIVES) DECREASED INCIDENCE AND/OR INTENSITY OF BOTH UNDESIRED EFFECTS BY DAMPENING OF THE PEAKS IN DRUG CONCENTRATION) DISADVANTAGES DOSAGE FORM MAY FAIL, AND “DOSE DUMPING” WITH RESULTING TOXICITY ABUSE (CRUSHING AND SNORTING THE DELAYED-RELEASE TABLETS RESULTS IN A RAPID RELEASE OF THE DRUG, INCREASED ABSORPTION, AND HIGH PEAK SERUM CONCENTRATIONS) SUBLINGUAL AND BUCCAL ADMINISTRATION ABSORPTION FROM THE ORAL MUCOSA VENOUS DRAINAGE FROM THE MOUTH IS TO THE SUPERIOR VENA CAVA, BYPASSING THE PORTAL CIRCULATION AND THEREBY PROTECTING THE DRUG FROM RAPID INTESTINAL AND HEPATIC FIRST-PASS METABOLISM. DRUGMUST BE NON-IONIC AND HAVE VERY HIGH LIPID SOLUBILITY FOR VERY RAPID ABSORPTION TRANSDERMAL, TOPICAL ADMINISTRATION NOT ALL DRUGS READILY PENETRATE THE INTACT SKIN. ABSORPTION IS DEPENDENT ON: SURFACE AREA OVER WHICH THEY ARE APPLIED AND THEIR LIPID SOLUBILITY BECAUSE THE EPIDERMIS BEHAVES AS A LIPID BARRIER THE DERMIS, HOWEVER, IS FREELY PERMEABLE TO MANY SOLUTES; CONSEQUENTLY, SYSTEMIC ABSORPTION OCCURS MUCH MORE READILY THROUGH ABRADED, BURNED, OR DENUDED SKIN INFLAMMATION AND OTHER CONDITIONS THAT INCREASE CUTANEOUS BLOOD FLOW SUSPENDING THE DRUG IN AN OILY VEHICLE AND RUBBING THE RESULTING PREPARATION INTO THE SKIN BECAUSE HYDRATED SKIN IS MORE PERMEABLE THAN DRY SKIN, THE DOSAGE FORM MAY BE MODIFIED, OR AN OCCLUSIVE DRESSING MAY BE USED TO FACILITATE ABSORPTION RECTAL ADMINISTRATION APPROXIMATELY 50% OF THE DRUG THAT IS ABSORBED FROM THE RECTUM WILL BYPASS THE LIVER; THE POTENTIAL FOR HEPATIC FIRST- PASS METABOLISM THUS IS LESS THAN THAT FOR AN ORAL DOSE; FURTHERMORE, A MAJOR DRUG METABOLISM ENZYME, CYP3A4, IS PRESENT IN THE UPPER INTESTINE BUT NOT IN THE LOWER INTESTINE. HOWEVER, RECTAL ABSORPTION CAN BE IRREGULAR AND INCOMPLETE, AND CERTAIN DRUGS CAN CAUSE IRRITATION OF THE RECTAL MUCOSA PARENTERAL ADMINISTRATION THE ROUTES OF PARENTERAL ADMINISTRATION ARE INTRAVENOUS, INTRAMUSCULAR SUBCUTANEOUS INTRAARTERIAL INTRATHECAL ABSORPTION FROM SUBCUTANEOUS AND INTRAMUSCULAR SITES OCCURS BY SIMPLE DIFFUSION ALONG THE GRADIENT FROM DRUG DEPOT TO PLASMA. THE RATE IS LIMITED BY: AREA OF THE ABSORBING CAPILLARY MEMBRANES, AND SOLUBILITY OF THE SUBSTANCE IN THE INTERSTITIAL FLUID DRUGS ADMINISTERED INTO THE SYSTEMIC CIRCULATION BY ANY ROUTE, EXCLUDING THE INTRA-ARTERIAL ROUTE, ARE SUBJECT TO POSSIBLE FIRST- PASS ELIMINATION IN THE LUNG PRIOR TO DISTRIBUTION TO THE REST OF THE BODY. THE LUNGS ALSO SERVE AS A FILTER FOR PARTICULATE MATTER THAT MAY BE GIVEN INTRAVENOUSLY, AND THEY PROVIDE A ROUTE OF ELIMINATION FOR VOLATILE SUBSTANCES  ADVANTAGES DRUG TO BE DELIVERED IS IN ITS ACTIVE FORM AVAILABILITY USUALLY IS MORE RAPID, EXTENSIVE, AND PREDICTABLE EFFECTIVE DOSE CAN THEREFORE BE DELIVERED MORE ACCURATELY IN EMERGENCY THERAPY AND WHEN A PATIENT IS UNCONSCIOUS, UNCOOPERATIVE, OR UNABLE TO RETAIN ANYTHING GIVEN BY MOUTH, PARENTERAL THERAPY MAY BE A NECESSITY DISADVANTAGES ASEPSIS MUST BE MAINTAINED, AND THIS IS OF PARTICULAR CONCERN WHEN DRUGS ARE GIVEN OVER TIME, SUCH AS IN INTRAVENOUS OR INTRATHECAL ADMINISTRATION; PAIN MAY ACCOMPANY THE INJECTION; AND IT IS SOMETIMES DIFFICULT FOR PATIENTS TO PERFORM THE INJECTIONS THEMSELVES IF SELF-MEDICATION IS NECESSARY  INTRAVENOUS FACTORS LIMITING ABSORPTION ARE CIRCUMVENTED BY INTRAVENOUS INJECTION OF DRUGS IN AQUEOUS SOLUTION BECAUSE BIOAVAILABILITY IS COMPLETE AND RAPID DRUG DELIVERY IS CONTROLLED AND ACHIEVED WITH AN ACCURACY AND IMMEDIACY CERTAIN IRRITATING SOLUTIONS CAN BE GIVEN ONLY IN THIS MANNER BECAUSE THE DRUG, IF INJECTED SLOWLY, IS GREATLY DILUTED BY THE BLOOD UNFAVORABLE REACTIONS CAN OCCUR BECAUSE HIGH CONCENTRATIONS OF DRUG MAY BE ATTAINED RAPIDLY IN BOTH PLASMA AND TISSUES DRUGS IN AN OILY VEHICLE, THOSE THAT PRECIPITATE BLOOD CONSTITUENTS OR HEMOLYZE ERYTHROCYTES, AND DRUG COMBINATIONS THAT CAUSE PRECIPITATES TO FORM MUST NOT BE GIVEN BY THIS ROUTE  INTRAMUSCULAR DRUGS IN AQUEOUS SOLUTION ARE ABSORBED QUITE RAPIDLY AFTER INTRAMUSCULAR INJECTION DEPENDING ON: RATE OF BLOOD FLOW TO THE INJECTION SITE LOCAL HEATING, MASSAGE, OR EXERCISE. GENERALLY, THE RATE OF ABSORPTION FOLLOWING INJECTION OF AN AQUEOUS PREPARATION INTO THE DELTOID OR VASTUS LATERALIS IS FASTER THAN WHEN THE INJECTION IS MADE INTO THE GLUTEUS MAXIMUS. RATE IS PARTICULARLY SLOWER FOR FEMALES AFTER INJECTION INTO THE GLUTEUS MAXIMUS DUE TO DIFFERENT DISTRIBUTION OF SUBCUTANEOUS FAT IN MALES AND FEMALES AND BECAUSE FAT IS RELATIVELY POORLY PERFUSED. SUBSTANCES TOO IRRITATING TO BE INJECTED SUBCUTANEOUSLY SOMETIMES MAY BE GIVEN INTRAMUSCULARLY  SUBCUTANEOUS INJECTION INTO A SUBCUTANEOUS SITE CAN BE DONE ONLY WITH DRUGS THAT ARE NOT IRRITATING TO TISSUE; OTHERWISE, SEVERE PAIN, NECROSIS, AND TISSUE SLOUGHING MAY OCCUR. RATE OF ABSORPTION FOLLOWING SUBCUTANEOUS INJECTION OF A DRUG OFTEN IS SUFFICIENTLY CONSTANT AND SLOW TO PROVIDE A SUSTAINED EFFECT INCORPORATION OF A VASOCONSTRICTOR AGENT IN A SOLUTION OF A DRUG TO BE INJECTED SUBCUTANEOUSLY ALSO RETARDS ABSORPTION  INTRA-ARTERIAL OCCASIONALLY, A DRUG IS INJECTED DIRECTLY INTO AN ARTERY TO LOCALIZE ITS EFFECT IN A PARTICULAR TISSUE OR ORGAN, SUCH AS IN THE TREATMENT OF LIVER TUMORS AND HEAD/NECK CANCERS INTRATHECAL BLOOD-BRAIN BARRIER AND THE BLOOD-CEREBROSPINAL FLUID (CSF) BARRIER OFTEN PRECLUDE OR SLOW THE ENTRANCE OF DRUGS INTO THE CNS. WHEN LOCAL AND RAPID EFFECTS OF DRUGS ON THE MENINGES OR CEREBROSPINAL AXIS ARE DESIRED, AS IN SPINAL ANESTHESIA OR TREATMENT OF ACUTE CNS INFECTIONS, DRUGS SOMETIMES ARE INJECTED DIRECTLY INTO THE SPINAL SUBARACHNOID SPACE PULMONARY ADMINISTRATION PROVIDED THAT THEY DO NOT CAUSE IRRITATION, GASEOUS AND VOLATILE DRUGS MAY BE INHALED AND ABSORBED THROUGH THE PULMONARY EPITHELIUM AND MUCOUS MEMBRANES OF THE RESPIRATORY TRACT ACCESS TO THE CIRCULATION IS RAPID BY THIS ROUTE BECAUSE THE LUNG’S SURFACE AREA IS LARGE SOLUTIONS OF DRUGS CAN BE ATOMIZED AND THE FINE DROPLETS IN AIR (AEROSOL) INHALED ADVANTAGES ALMOST INSTANTANEOUS ABSORPTION OF A DRUG INTO THE BLOOD AVOIDANCE OF HEPATIC FIRST-PASS LOSS IN THE CASE OF PULMONARY DISEASE, LOCAL APPLICATION OF THE DRUG AT THE DESIRED SITE OF ACTION BIOEQUIVALENCE DRUG PRODUCTS ARE CONSIDERED TO BE PHARMACEUTICAL EQUIVALENTS IF THEY CONTAIN THE SAME ACTIVE INGREDIENTS, AND ARE IDENTICAL IN STRENGTH OR CONCENTRATION, DOSAGE FORM, AND ROUTE OF ADMINISTRATION RATES AND EXTENTS OF BIOAVAILABILITY OF THE ACTIVE INGREDIENT IN THE TWO PRODUCTS ARE NOT SIGNIFICANTLY DIFFERENT UNDER SUITABLE TEST CONDITIONS BIOAVAILABILITY FRACTION OF DRUG ABSORBED AS SUCH INTO THE SYSTEMIC CIRCULATION. IF THE METABOLIC OR EXCRETORY CAPACITY OF THE LIVER AND THE INTESTINE FOR THE DRUG IS LARGE, BIOAVAILABILITY WILL BE REDUCED SUBSTANTIALLY (FIRST-PASS EFFECT) DISTRIBUTION OF DRUGS FOLLOWING ABSORPTION OR SYSTEMIC ADMINISTRATION INTO THE BLOODSTREAM, A DRUG DISTRIBUTES INTO INTERSTITIAL AND INTRACELLULAR FLUIDS. VOLUME OF DISTRIBUTION THE VOLUME OF DISTRIBUTION (VD) IS A PHARMACOKINETIC PARAMETER REPRESENTING AN INDIVIDUAL DRUG'S PROPENSITY TO EITHER REMAIN IN THE PLASMA OR REDISTRIBUTE TO OTHER TISSUE COMPARTMENTS. THELARGER THE VOLUME OF DISTRIBUTION, THE MORE LIKELY THAT THE DRUG IS FOUND IN THE TISSUES OF THE BODY. THE SMALLER THE VOLUME OF DISTRIBUTION, THE MORE LIKELY THAT THE DRUG IS CONFINED TO THE CIRCULATORY SYSTEM. DETERMINANTS OF THE RATE OF DELIVERY AND POTENTIAL AMOUNT OF DRUG DISTRIBUTED INTO TISSUES CARDIAC OUTPUT REGIONAL BLOOD FLOW CAPILLARY PERMEABILITY MOLECULAR SIZE DEGREE OF IONIZATION LIPID SOLUBILITY BINDING TO SERUM PROTEINS TISSUE VOLUME PLASMA PROTEINS MANYDRUGS CIRCULATE IN THE BLOODSTREAM BOUND TO PLASMA PROTEINS (CARRIER PROTEINS) ALBUMIN IS A MAJOR CARRIER FOR ACIDIC DRUGS; Α1-ACID GLYCOPROTEIN BINDS BASIC DRUGS; BINDING IS USUALLY REVERSIBLE; COVALENT BINDING OF REACTIVE DRUGS SUCH AS ALKYLATING AGENTS OCCURS OCCASIONALLY. IN ADDITION TO THE BINDING OF DRUGS TO CARRIER PROTEINS SUCH AS ALBUMIN, CERTAIN DRUGS MAY BIND TO PROTEINS THAT FUNCTION AS SPECIFIC HORMONE CARRIER PROTEINS SEX HORMONE– BINDING GLOBULIN - ESTROGEN OR TESTOSTERONE THYROXIN-BINDING GLOBULIN THYROID HORMONE  BINDINGOF A DRUG TO PLASMA PROTEINS LIMITS ITS CONCENTRATION IN TISSUES AND AT ITS SITE OF ACTION BECAUSE ONLY UNBOUND DRUG IS IN EQUILIBRIUM ACROSS MEMBRANES. AFTER DISTRIBUTION EQUILIBRIUM IS ACHIEVED, THE CONCENTRATION OF ACTIVE, UNBOUND DRUG IN INTRACELLULAR WATER IS THE SAME AS THAT IN PLASMA EXCEPT WHEN CARRIER-MEDIATED TRANSPORT IS INVOLVED TISSUE BINDING FAT AS RESERVOIR MANY LIPID-SOLUBLE DRUGS ARE STORED BY PHYSICAL SOLUTION IN THE NEUTRAL FAT. HENCE FAT MAY SERVE AS A RESERVOIR FOR LIPID-SOLUBLE DRUGS. REDISTRIBUTION TERMINATION OF DRUG EFFECT AFTER WITHDRAWAL OF A DRUG USUALLY IS BY METABOLISM AND EXCRETION REDISTRIBUTION OF THE DRUG FROM ITS SITE OF ACTION INTO OTHER TISSUES OR SITES BLOOD-BRAIN-BARRIER BRAIN CAPILLARY ENDOTHELIAL CELLS HAVE CONTINUOUS TIGHT JUNCTIONS; THEREFORE, DRUG PENETRATION INTO THE BRAIN DEPENDS ON TRANSCELLULAR RATHER THAN PARACELLULAR TRANSPORT. THE LIPID SOLUBILITY OF THE NONIONIZED AND UNBOUND SPECIES OF A DRUG IS THEREFORE AN IMPORTANT DETERMINANT OF ITS UPTAKE BY THE BRAIN IN GENERAL, THE BLOOD-BRAIN BARRIER’S FUNCTION IS WELL MAINTAINED; HOWEVER, MENINGEAL AND ENCEPHALIC INFLAMMATION INCREASES LOCAL PERMEABILITY PLACENTAL TRANSFER OF DRUG LIPID SOLUBILITY, EXTENT OF PLASMA BINDING, AND DEGREE OF IONIZATION OF WEAK ACIDS AND BASES ARE IMPORTANT GENERAL DETERMINANTS IN DRUG TRANSFER ACROSS THE PLACENTA  IN GENERAL, BIOTRANSFORMATION REACTIONS GENERATE MORE POLAR, INACTIVE METABOLITES METABOLIS THAT ARE READILY EXCRETED FROM THE BODY M OF DRUGS LIPOPHILIC COMPOUNDS FILTERED THROUGH THE GLOMERULUS ARE REABSORBED INTO THE SYSTEMIC CIRCULATION DURING PASSAGE THROUGH THE RENAL TUBULES.  DRUG METABOLISM OR BIOTRANSFORMATION REACTIONS ARE CLASSIFIED AS EITHER: PHASE I FUNCTIONALIZATION REACTIONS (E.G., OXIDATION, REDUCTION, HYDROLYSIS) PHASE II BIOSYNTHETIC REACTIONS (E.G., CONJUGATION) PHASE I FUNCTIONALIZATION REACTIONS (E.G. OXIDATION, REDUCTION, HYDROLYSIS) INTRODUCE OR EXPOSE A FUNCTIONAL REACTIVE GROUP, SUCH AS HYDROXYL GROUP, ON THE PARENT COMPOUND THIS GROUP SERVES AS THE POINT OF ATTACK FOR THE CONJUGATING SYSTEM TO ATTACH A SUBSTITUENT, SUCH AS GLUCURONIDE THE LIVER IS ESPECIALLY IMPORTANT IN PHASE 1 REACTIONS. MANY HEPATIC DRUG - METABOLIZING ENZYMES, INCLUDING CYP ENZYMES (CYTOCHROME P450 SYSTEM), ARE EMBEDDED IN THE SMOOTH ENDOPLASMIC RETICULUM. POLAR DRUGS ARE, AT LEAST PARTLY, EXCRETED UNCHANGED IN THE URINE. NOT ALL DRUG OXIDATION REACTIONS INVOLVE THE P450 SYSTEM. SOME DRUGS ARE METABOLIZED IN PLASMA, LUNG, OR GUT  P450 CAN BE INHIBITED OR INDUCED ENZYME INHIBITION, PARTICULARLY OF CYP ENZYMES, SLOWS THE METABOLISM AND HENCE INCREASES THE ACTION OF OTHER DRUGS INACTIVATED BY THE ENZYME INDUCTION OF P450 ENZYMES CAN GREATLY ACCELERATE HEPATIC DRUG METABOLISM. ENZYME INDUCTION CAN INCREASE DRUG TOXICITY AND CARCINOGENICITY, BECAUSE SEVERAL PHASE 1 METABOLITES ARE TOXIC OR CARCINOGENIC.  PHASE I REACTIONS GENERALLY RESULT IN THE LOSS OF PHARMACOLOGICAL ACTIVITY, ALTHOUGH THERE ARE EXAMPLES OF RETENTION OR ENHANCEMENT OF ACTIVITY PRODRUGS ARE PHARMACOLOGICALLY INACTIVE COMPOUNDS DESIGNED TO MAXIMIZE THE AMOUNT OF THE ACTIVE SPECIES THAT REACHES ITS SITE OF ACTION. INACTIVE PRODRUGS ARE CONVERTED RAPIDLY TO BIOLOGICALLY ACTIVE METABOLITES OFTEN BY THE HYDROLYSIS OF AN ESTER OR AMIDE LINKAGE PHASE II BIOSYNTHETIC REACTIONS (E.G. CONJUGATION) PHASE 2 REACTIONS TAKE PLACE MAINLY IN THE LIVER MANY CONJUGATION REACTIONS OCCUR IN THE LIVER, BUT OTHER TISSUES, SUCH AS LUNG AND KIDNEY, ARE ALSO INVOLVED PHASE II CONJUGATION REACTIONS LEAD TO THE FORMATION OF A COVALENT LINKAGE BETWEEN A FUNCTIONAL GROUP ON THE PARENT COMPOUND OR PHASE I METABOLITE, AND ENDOGENOUSLY DERIVED GLUCURONIC ACID, SULFATE, GLUTATHIONE, AMINO ACIDS, OR ACETATE THESE HIGHLY POLAR CONJUGATES GENERALLY ARE INACTIVE AND ARE EXCRETED RAPIDLY IN THE URINE AND FECES SOME CONJUGATED PRODUCTS ARE EXCRETED VIA BILE, ARE REACTIVATED IN THE INTESTINE AND THEN REABSORBED FIRST-PASS METABOLISM FOLLOWING ORAL ADMINISTRATION OF A DRUG, A SIGNIFICANT PORTION OF THE DOSE MAY BE METABOLICALLY INACTIVATED IN EITHER THE INTESTINAL EPITHELIUM OR THE LIVER BEFORE THE DRUG REACHES THE SYSTEMIC CIRCULATION. SIGNIFICANTLY LIMITS THE ORAL AVAILABILITY OF HIGHLY METABOLIZED DRUGS  DRUGS ARE ELIMINATED FROM THE BODY EITHER EXCRETIO UNCHANGED BY THE PROCESS N OF OF EXCRETION OR CONVERTED TO METABOLITES DRUGS THE KIDNEY IS THE MOST IMPORTANT ORGAN FOR EXCRETING DRUGS AND THEIR METABOLITES  SUBSTANCES EXCRETED IN THE FECES ARE PRINCIPALLY UNABSORBED ORALLY INGESTED DRUGS OR DRUG METABOLITES EXCRETED EITHER IN THE BILE AND NOT REABSORBED, OR SECRETED DIRECTLY INTO THE INTESTINAL TRACT AND NOT REABSORBED EXCRETION OF DRUGS IN BREAST MILK IS IMPORTANT BECAUSE THE EXCRETED DRUGS ARE POTENTIAL SOURCES OF UNWANTED PHARMACOLOGICAL EFFECTS IN THE NURSING INFANT EXCRETION FROM THE LUNG IS IMPORTANT MAINLY FOR THE ELIMINATION OF ANESTHETIC GASES ZERO-ORDER ELIMINATION IMPLIES THAT THE RATE OF ELIMINATION IS CONSTANT REGARDLESS OF CONCENTRATION FIRST-ORDER ELIMINATION INDICATES THAT THE RATE OF ELIMINATION IS PROPORTIONAL TO THE CONCENTRATION (I.E., THE HIGHER THE CONCENTRATION, THE GREATER THE AMOUNT OF DRUG ELIMINATED PER UNIT TIME) CLEARANCE DERIVED IN UNITS OF VOLUME/TIME MEASURE OF THE BODY’S EFFICIENCY IN ELIMINATING DRUG FROM THE SYSTEMIC CIRCULATION DEFINEDAS THE VOLUME OF PLASMA CONTAINING THE AMOUNT OF SUBSTANCE THAT IS REMOVED FROM THE BODY BY THE KIDNEYS IN UNIT TIME CHANGESIN PROTEIN BINDING OF A DRUG MAY AFFECT ITS CLEARANCE AS WELL AS ITS VOLUME OF DISTRIBUTION ELIMINATION HALF-LIFE (T1/2) TIMEIT TAKES FOR THE PLASMA CONCENTRATION TO BE REDUCED BY 50%. AS CLEARANCE DECREASES, OWING TO A DISEASE PROCESS, E.G., T1/2 WOULD BE EXPECTED TO INCREASE STEADY STATE REFERS TO THE SITUATION WHERE THE OVERALL INTAKE OF A DRUG IS FAIRLY IN DYNAMIC EQUILIBRIUM WITH ITS ELIMINATION RENAL EXCRETION RENAL EXCRETION OF UNCHANGED DRUG IS A MAJOR ROUTE OF ELIMINATION FOR 25–30% OF DRUGS ADMINISTERED TO HUMANS EXCRETION OF DRUGS AND METABOLITES IN THE URINE INVOLVES THREE DISTINCT PROCESSES: GLOMERULAR FILTRATION THE AMOUNT OF DRUG ENTERING THE TUBULAR LUMEN BY FILTRATION DEPENDS ON THE GLOMERULAR FILTRATION RATE AND THE EXTENT OF PLASMA BINDING OF THE DRUG; ONLY UNBOUND DRUG IS FILTERED.  PASSIVE TUBULAR REABSORPTION IF THE TUBULE IS FREELY PERMEABLE TO DRUG MOLECULES, SOME 99% OF THE FILTERED DRUG WILL BE REABSORBED PASSIVELY DOWN THE RESULTING CONCENTRATION GRADIENT LIPID-SOLUBLE DRUGS ARE THEREFORE EXCRETED POORLY, WHEREAS POLAR DRUGS OF LOW TUBULAR PERMEABILITY REMAIN IN THE LUMEN AND BECOME PROGRESSIVELY CONCENTRATED AS WATER IS REABSORBED THE ION-TRAPPING EFFECT MEANS THAT A BASIC DRUG IS MORE RAPIDLY EXCRETED IN AN ACID URINE THAT FAVORS THE CHARGED FORM AND THUS INHIBITS REABSORPTION. CONVERSELY, ACIDIC DRUGS ARE MOST RAPIDLY EXCRETED IF THE URINE IS ALKALINE  ACTIVE TUBULAR SECRETION DRUG MOLECULES ARE TRANSFERRED TO THE TUBULAR LUMEN BY TWO INDEPENDENT AND RELATIVELY NON- SELECTIVE CARRIER SYSTEMS – ORGANIC ANION TRANSPORTER (OAT) AND ORGANIC CATION TRANSPORTER (OCT) BECAUSE AT LEAST 80% OF THE DRUG DELIVERED TO THE KIDNEY IS PRESENTED TO THE CARRIER, TUBULAR SECRETION IS POTENTIALLY THE MOST EFFECTIVE MECHANISM OF RENAL DRUG ELIMINATION  IN NEONATES, RENAL FUNCTION IS LOW COMPARED WITH BODY MASS BUT MATURES RAPIDLY WITHIN THE FIRST FEW MONTHS AFTER BIRTH DURING ADULTHOOD, THERE IS A SLOW DECLINE IN RENAL FUNCTION, ~1% PER YEAR IN ELDERLY PATIENTS A SUBSTANTIAL DEGREE OF FUNCTIONAL IMPAIRMENT MAY BE PRESENT BILIARY AND FECAL EXCRETION TRANSPORTERS ARE ALSO PRESENT IN THE CANALICULAR MEMBRANE OF THE HEPATOCYTE, AND THESE ACTIVELY SECRETE DRUGS AND METABOLITES INTO BILE. ULTIMATELY, DRUGS AND METABOLITES PRESENT IN BILE ARE RELEASED INTO THE GI TRACT DURING THE DIGESTIVE PROCESS BECAUSE SECRETORY TRANSPORTERS ALSO ARE EXPRESSED ON THE APICAL MEMBRANE OF ENTEROCYTES, DIRECT SECRETION OF DRUGS AND METABOLITES MAY OCCUR FROM THE SYSTEMIC CIRCULATION INTO THE INTESTINAL LUMEN  SUBSEQUENTLY, DRUGS AND METABOLITES CAN BE REABSORBED BACK INTO THE BODY FROM THE INTESTINE, WHICH, IN THE CASE OF CONJUGATED METABOLITES SUCH AS GLUCURONIDES, MAY REQUIRE THEIR ENZYMATIC HYDROLYSIS BY THE INTESTINAL MICROFLORA. SUCH ENTEROHEPATIC RECYCLING, IF EXTENSIVE, MAY PROLONG SIGNIFICANTLY THE PRESENCE OF A DRUG (OR TOXIN) AND ITS EFFECTS WITHIN THE BODY PRIOR TO ELIMINATION BY OTHER PATHWAYS. EXCRETION BY OTHER ROUTES EXCRETION OF DRUGS INTO SWEAT, SALIVA, AND TEARS IS QUANTITATIVELY UNIMPORTANT ELIMINATION BY THESE ROUTES DEPENDS MAINLY ON DIFFUSION OF THE NON-IONIZED LIPID-SOLUBLE FORM OF DRUGS THROUGH THE EPITHELIAL CELLS OF THE GLANDS ALTHOUGH EXCRETION INTO HAIR AND SKIN IS QUANTITATIVELY UNIMPORTANT, SENSITIVE METHODS OF DETECTION OF DRUGS IN THESE TISSUES HAVE FORENSIC SIGNIFICANCE ADMINISTRATION OF DRUGS TO BREAST-FEEDING WOMEN CARRIES THE GENERAL CAUTION THAT THE SUCKLING INFANT WILL BE EXPOSED TO SOME EXTENT TO THE MEDICATION AND/OR ITS METABOLITES END