8. PROTEIN - BINDING OF DRUGS Bi Drugs are bound to several plasma constituents including albumin, ay-acid glycoprotein (AGP), lipoproteins and globulins. Apart from the specific binding proteins like transcortin for prednisolone and thyzoxine-binding the major proteins of givbulin, albumin and g)-acid importance With Fespect fo drug binding; importance with respect 9 ees. Albumin is present in lasma of healthy individuals at a concentration of ap pronimately 40 ~The molecular weight of albumin is| positions of the chain. ee a ee Site I and Site IJ. Site I (alsa known as the wariarin site) binds lic di: suchas warfarin But can also bind basic drugs provided they are in the Unionised form. Site lis also thought to be associated with the binding of fatty acids. Site I, like Site I, is hydrophobic in nature and.ishnownas the: diazepam or benzodiazepine site. Compared to albumin, o,-acid glycoprotein is present at a lo concentration in plasma, Varying beti 1.55 and 1.4 g li! Asingle Fydrophobic, high atin binding ste or base drugs oni), is thought to be present on the protein molecule, The clinical importance of binding to c-acid glycoprotein is uncertain as tis usually present atlow ie 4p aeeentation, However, the large increase in the concentration in respor ogiatromintons particularly those 7 on page FS may be potentially significant. In this context itis worth noting that both the antiarrhythmic drug, lignocaine (lidocaine), and the analgesic drug, a eS pnisconmony wa during bout, av ston bound to a-acid glycoprotein. “Among the various tissue components of importance in drug binding » in (a binding protein for various dn cotticosteroi bilirubin) which has been isolated in the tubule cells of the kidney and the small intestine, DNA has been reported to bind a as, folate an| where IC] - molar free drug concentration PI - molar free protein concentration [cP] molar concentration of drug protein complex ‘At equilibrium the rate of the forward reaction is equal to the rate of the reverse reaction, ‘Therefore, (CHIP = and where KA js the affinity constant. The same ratio will be obtained if the molar concentrations of drug are substituted with actual concentrations. » ‘The concentration of unbound drug will be equal to fu, Cp and concentration of drug bound to the protein will be (I-fu,) Cp where fps the fraction of unbound drug in the plasma, aS pr ———— Therefore, (1 = fu) Cp 1 = fy .) n that Hinity consiant ofthe &and low extraction ratio drugs in Sections 6.3 and 6.4. Changes in the BANGing oF drugs fo proteins in the plasma and tissues that might OCCur as 2 ‘Result of disease will also aifoc! the apparent volume of distribution of some age ‘The lipophilicity of the and the affinity of the drug molecule £ iesue and plasma protein binding sites determine the degree of tissue and plasma binding. Three situations can therefore exist depending on the Gifferential affinity for ssue and plasma bindings sites: © adrug having higher affinity for plasma proteins than for tissue proteins will be preferentially distributed in the plasma comparim: ‘and consequently have a low apparent volume of distribution, © warfarin or phenylbutazone. for tissue protein binding sit © adrug having a higher affi 5 will be ‘widely distributed exavasculanly, therefore having a high apparent volumé of distribution, e.g, chloroquine (V = 235 litre kg”), « anintermediate situation may exist where a drug has a higher affinity for a particular tissue or organ than for the plasma proteins, but has a higher affinity for the plasma proteins than for the rest of the tissues in the body. Examples of this intermediate situation include: (propranolol, which is highly extracted from the iver, (2) methotrexate, which is preferentially concentrated in tissues with high level of dihydrofolate reductase, or (ii) barbiturates (e.g, thiopentone) used for induction of anaesthes which distribute to the lipophilic cerebral tissue first, ther their anaesthetic effect shorily after administration, but redistribute to the rest of the body tissues at later times post adminis Consider the total amount of drug in the body (V Cp) as be! @ w in the plasma (Vp Cp) yy fluids and= unbound fraction of drug in plasma = unbound fraction of drug in tissue = unbound concentration of drug in plasma = unbound concentration of drug in tissue ‘Assuming that there is no barrier to the diffusion of unbound drug throwshout the body, at distribution equilibrium the concentration of unbound drug in plasma and tissue should be equivalent Therefore, a. & oO Toy (8.3) From this relationship it can be seen that for a drug that is highly protein pound in the plasma but undergoes little or no binding in the tissues, (Le fa, =O and fit = 1), the smallest apparent volume of distribution vil be Giuerved and should approximate to the plasma volume, Convérselifigr 8 rug that s highly tissue bound, the plasma volume of approximately. 3.0 thes is small compared to the tissue volume and, therefore, negligible, = faz approaches 0, the volume of distribution becomes dependent on the free friction in the plasma. This relationship, however, does not account for she ‘hat that albumin, the major binding protein for acidic drugs, is distributed toa major extent extravascularly. The extravascularintravasculas albumin ratio is normally 1.43:1 indicating that so ‘body content of Tocun is found in the extravascular compartment. The following | _selationship fr the volume of distribu Sunt thi i e sion rates and, wuscie and skin) he8.4.2 Low extraction ratio drugs effects as only these drug molecules are free to combine with the appropriate receptors. Ther a displacement interaction wer a high extraction ratio drug it might be necessary to reduc increase the dosing interval so as to avoid toxicity to persist with ose or Fora low extraction ratio drug the clearance will increase with a decrease in binding of drug to blood /plasma proteins (see Section 6.4.2). The increased clearance of drug will result in a lower total plasma concentration at steady state. although the apparent volume of distribution will have increased, the lower value for Cp,, means that the amount of drug in the body at steady state will be much the same. Therefore, according to equation (8.3) the ‘oncentration of unbound drug in the plasma will be unchanged. The need fora change in the dosage regimen would, therefore, be most unlikely with a low extraction ratio drug under these circumstances. Various disease states and processes can affect the amount of protein present in the plasma which is available for binding drugs. The liver acts as the source of albumin and c,-acid glycoprotein and therefore during chronic liver disease and during malnutritionone can expect a decrease in the plasma concentrations of these two proteins. Also, during renal disease the integrity of the glomerulus may be lost and sighificant amounts of pl proteins be excreted in the urine. Bums patients can also experiénce Iifgs of large amounts of plasma proteins. As mentioned previously, during .", conditions of stress, plasma levels of c,-acid glycoprotein will increase. Some conditions in which albumin and o,-acid glycoprotein plasma * concentrations are altered.When the normal steady state target concentration of drug ( Cp,.) and the | normal fraction of unbound drug (fu,) are known, the concentration of ‘unbound drug required (C y,..) can be calculated, In adjusting drug dosage resimens to allow for altered plasma protein binding of drug, the aim is to achieve the same plasma concentration of | Gnbound drug as in an individual with normal drug binding: a = fu, Cp” = fi, CPs where * indicates the values for the patient with altered drug bin “Assuming the affinity constant to remain the same, then from equation (8.1) we have ———. — (3.6) cos (Actual protein concentrations can replace molar concentration as the ratio remains constant). Substituting for fu," in equation (6.6) and rearranging sives: aa eel Pleat 7 : fa - tap 2] + 2} 7) Cpa = CPys| | ~ My) Gr} My where © pais the new target concentration of concentration.value increases (7) decreases (1) or remains essentially unc & Given the following changes in protein binding for a low extraction ratio 8 comp! following Table indicating whether a given parameter anged (=), Single iv. bolus dose iv. infusion Initial fy fur | AUC. a cone’ Coy | Cy, o rickets in Lag Se Pee > wel Sie ¢ qe v decmetwe have assume: Inall the pharmacokinetics that we have discussed so Zar, linear (apparent first order) disposition processes. To see w! assumption is valid for most drugs, and to understand those situatio: where it is an oversimpiification, it is necessary to consider the Michae! Menten equation. y this entation, Since it was first introduced to explain enzyme kinetics of the process, the Michaelis-Menten equation has been applied to many enzymatic reactions. The rate of the reaction is dependent upon several parameters as shown below Vimax_* © ate of Reaction == 22 ao Rasen Km + © where 2 Viggci8 the maximum rate of velocity of the reaction. This parameter will be, in part, a function of the total amount of enzyme available to take part in the reaction. * Cis the concentration of the reacting compound, © Kmisa constant known as the Michaelis-Menten constant. This is related to the affinity of the compound for the enzyme and will be defined further below. aes “bs The reason that this type of reaction is known as nonlinear is that the rate'gf - reaction is not linearly related to the concentration of the reacting 7 compound, Therefore, a graph of rate of reaction versus concentration, unlike that for a first order process, will not be linear. ‘The Michaelis-Menten equation can be applied to enzyme controlled reactions involving the metabolism of drugs: Vmax X CP | | Rate of Metabolism = = = 2) | Rate of Metabo ac 3 i 8.1.1 Km >> ¢ to equationsFrom this it is seen that Venax = cearence For most drugs we are justified in using this approximation of the Michaelis: Menten equation that represents clearance (CL) as a constant because the | plasma concentrations seen with normal therapeutic use of the drugs are ‘mall relative to the Km values of the enzymes responsible for their metabolism. 9.12 Cp >> Km" | When the plasma concentration of drug is large relative to Kim (he. Cp >> Km), the contribution of Km to the denominator of equation (9.2) is negligible and the rate of metabolism is given as follo rate of metabolism = Vinax (9.5) | Equation (9.5) represents a zero order Kinetic process, i.e the rate of | metabolism is a constant and, therefore, independent of the plasma aencentration of drug, Its this property of equation (9.2) that has given rise to the torm eapacity-limited as ti possible with high concentrations of dinig to reach the point where the enzyme is working at maximum velocity | and any further increase in drug concentration will have no additjanal effect | Gh the rate of metabolism of drug, Fortunately, this situation 3 extrortgly | care in connection with the elimination of drugs from the body. However, a | oe common situations that eich sneermediateBebween* | | apparent frst order and zero order kinetics when both Km and Cp maké a | contribution to the denominator of equation (9.2), For the remainder of this + | Seetion we will, therefore, concern ourselves with the full form of the Micha Menten equation. “am expression fr the clearance of drug can be obtained by dividing through of equation (2.2) by the plasma concentration of drag. THs wi sid n be seen ‘sely proportional to concentration so thTherefore. Rig = CL CPs Km + CP, and Because the relationship between the rate of elimination and the clearance of __adrug subject to capacity-limited metabolism is not linear, the relationship between the rate of drug administration and the mean steady state plasma concentration will not be linear. This is illustrated in Fig. 4 Css prt fi Vinax ation and Figure 4 The relationship between steady state plasme con | dosing rate for a drug exhibiting capacity-limited elimination‘The time to reach steady state will depend upon the values of V.,,, Kmand R,,; but it should also be noted that, as the dosing rate approaches the value Of Vinay the time to achi tion increases dramatically. 90% of the eventual steady state plasma conee As was the case with the time to steady state, there is no simple expression to describe the elimination hali-life of drugs subject to capacity-limited elimination, The following equation describes the time course of elimination for such drugs: Yeas + Cp” = Cpl) = BE x (9.190 where Cp" is the initial plasma concentration at time zero. The equation cannot be solved explicitly in terms of ‘Cp’, but must always be solved in terms of . The time for Cp” to decline to half of its original value will depend, not only on the values of Vi,qy, Km and V, but also on the value of Cp?; the larger the initial concentration, the longer will be the time taken for the concentration to fall by 50%. ° s Nonlinearity in the elimination of a drug can be due to a numberof H¥jprs * other than capacity-limited metabolism. Other possibilities include: "= | © amore rapid elimination of some compounds at high plasma concentration due to capacity-limited reabsorption within the kidnty tubules (e.g, riboflavine, cephaloridine) © an increasing rate of elimination over a period of time de to enzyme induction caused by the drug itself (eg. carbamazepine) changes in one or both of clearance and apparent volume of distribution and, consequently, in half-life also, due to sa in binding in the plasma or the tissues (e.g. disopytamide) ble iimination of to be nonlinand assuming the patient to have a population value for Km, a value for Venay C25 Be by sting into either of these equations. Then, knowing the desired target concentration, substituting for Km, Via, and | Cp,, into equation (9.7) allows the new dosing rate tc be calculated, When ‘two dosing rates together with the corresponding steady state plasma concentrations are available, estimates can be made of both Km and Vin the patient, This is done using either equation (9.7) or (9.8) and soiving by the method of simultaneous equations for Km and Ving. ag Example 1 ‘Steady state plasma phenytoin concentration = 7 mg litre" Corresponding dosing rate = 200 mg day Calculate a dosing rate to give a steady state concentration of 15 mg litre" | Assumea population value for Km = 4.2 mg litre" Substitute for Km, R,, and Cp,, in equation (9.7) and solve for V, = 320mgday? | Ria(Km + Cp) mx = Now substitute for Vi,4., Km and Cp,, in equation (9.7) and solve for Ry c : é max * CPs A Pl 2 R, a = 250mg day’ 4 Ay ia cco 50 mg Bt, It is important to check the new steady state level achieved with this, calculated dosing rate as it is based on an assumption regarding the value for Km in this patient. Example 2 (Steady state plasma phenytoin concentration Corresponding dosing rate = 200 mg day" | Gi) Steady state plasma phenytoin concentration Correspondis and si iging equation (9.7) 10 solve foF VinayTherefore, Vizg, = (40 Km +200) = 400 mg day? Substituting in equation (9.7) for V,,., Km and the required Cp,, (13 mg litre’) gives: 400 _x_15 SES + 00 med 5+ 15 es Rin It is important to measure the level achieved with this new dosing rate as it ‘was based on an assumption that the two measured levels were taken at steady state and this may not have been the case. Propranolol, theophylline and salicylic acid are all compounds where one or more of the metabolic routes is liable to be capacity-limited at p concentrations seen within the therapeutic range. Because of its wide therapeutic margin, this is not a problem with propranolol. In addition to the capacity-limited metabolic routes, salicylic acid also follows metabolic routes that obey apparent first order kinetics within the therapeutic range. Therefore, the nonlinearity does not cause problems in the clinical use of salicylates. Theophylline also has parallel apparent first order and capacity- limited metabolism, but, again, the nonlinearity does not cause problems clinically in adults. There is evidence, however, that the nonlinearity is. more pronounced in children so that careful mositoring is advisabfe when using the drug in this group of patients. 44, You are asked to advise on dosage adjustment in the following patient: Male - 56 years - 62 kg. Current dose of phenytoin: 250 mg daily. Serum phenytoin: 40 mol litre (10 ug ml). Number of fits in last month: 2. Previous history: phenytoin dose 200 mg daily; serum phenytoin: 24 umol litre? (6 ug ml"), What new dosage regimen would ¥ recommend? {ov opt 1S sy [ml18. COMPARTME: OPEN MODE! ‘Whereas the concepts of clearance and apparent volume of distribution measured a5 Varqq aT@ model independent, the equations that we have described for a single intravenous bolus dose (section 2.2), a constant rate intravenous infusion (section 3), single oral dose (section 4) and multiple dosing (section 5) are all based on the assumption that drug is distributed instantaneously. This is the basic assumption for what is known as an open ‘one compartment model; ‘one compartment’ because drug is assumed to distribute instantaneously, and ‘open’ because drug is eliminated from the compartment. In reality, distribution of drug takes a finite period of time. In the majority of cases the distribution is rapid relative to the elimination of the drug, so that the equations of a one compartment model are adequate for most clinical pharmacokinetic purposes. In this section we will look briefly at the ‘two compartment open model shown in Fig. 5 that allows for a finite period of distribution. | oy, ¥ Ke “4 Figure 5 A two compartment open body model |All transfer processes between compartments are considered to obey first order kinetics. The two compartments can be considered as a central compartment (compartment 1), made up of well perfused, rapidly equilibrating tissues, and a peripheral compart ‘partment 2) composed of less well perfused tissues, into which the drug moves more T iological f mpartments is not considered inVig = Vi + V2 0.7) Atsteady state the rate at which drug enters the peripheral compartment will be the same as the rate at which it leaves the peripheral compartment. Therefore, kp Va Cy V3 ‘Assuming the concentration of drug to be the same in both compartments at steady state (ie. C, = C,); (0.8) In this form the value for V,, is difficult to calculate as first one must determine the values of the micro-rate constants and the volume of the central compartment. The same value can be calculated relatively easify by, measuring the areas under two graphs obtained from data relating ta’a “Mt, single bolus intravenous dose of drug. The first area term isonethatwe .") + have diready encountered and know as AUC, the area under a graph of . plasma concentration versus time. The second area term is known as the area under the first moment curve and is abbreviated as AUMC. This refers to the area under a curve of Cp x t versus time and can be obtained using the appropriate trapezoidal, log trapezoidal and extrapolation equations shown 1 in Append auc {cpat10.5.1 Clearance 10.5.2 V, 10.5.3 Micro-rate constants 4 Area under curves (Clearance can be determined b y the method that we have seen previ (equruica (2.3), using measurement of the area under the eo Dy ‘UC In terms of the two compartment model, this is also equal to CL = kV, (0.10) The estimate of Vg, is not dependent upon estimating micro-rate const but can be determined, in the manner described previously in section with ‘beta’ replacing ‘K’ as the terminal elimination rate constant 2 ao Wy Of less value for routine clinical pharmacokinetics are the micro-rate 42 constants. However, ifalpha, beta, ‘A’ and ‘P’ are knows, itis a siuapie” [ rate constants from the following equations. Consider equation (10.1) at time zero, The initial concentration will then be equal to ‘A’ +B’, This gives a method of estimating the volume of the central compartment, V, 0.11) ove allows kyy to be determined #5 cl eee = AS 0.13) v Zwhere V; is the volume of the central compartment, k,, isa first order micro | rate constant describing transfer of drug from the peripheral to the central | compartment, and the terms ‘alpha’ (o) and ‘beta’ (B) are hybrid rate | constants that are complex functions of ky, kjz and kyo. (Equation (10.2 | should be compared with that for a one compartment model - equation 23). 12.2 Estimating | We have already meta biexponential equation in sections 4.2 and 4.3 when cipacend bete | considering first order absorption of drugs. The same arguments can be | definition, alpha is larger that beta. Therefore, as time increases, the | exponential term containing alpha will approach zero more rapidly than the exponential term containing beta. At later times equation (10.1) Py When Rig + CPy, = 6 mg litre" When Rig Cy = 10 mg tire,Therefore, ER " F=1-ER = 0.96 ig B is strongly bound to plasma proteins and is a low extraction ratio drug. Therefore, both total clearance and the required infusion rate will depend uponinirinsic clearance and plasma protein binding, which may be reduced in cirrhosis. Any decrease in livet blood flow which can also occuras a result of cirrhosis will have little ornoeffect onthe clearance ofa low extraction ratio drug. For the oral dose data AUC = 6.667 hours x mg lize!" a ‘Assuming clearance to remain constant Cly = CL, iw po 60 _ FD _ Fx 150 1000 Ree AUG! 6.667 0.667 ties bi“? 7000 x 130Substituting for Vinay (200 x Km_+_ 1200) 6 Km > 10 x 10 Solving for Km gives: 1 Km = 6 mg litre’ ‘Therefore, Vina ¥ 6 20 = Ere so that Vmax = 400 mg day“! Assuming a target mean steady state concentration of 15 mg litre Vinax * CPss 400 x 15 Rig Se eae 285 mg day . s co ty This is not a commonly available size of dose, therefore try 274mg day-1 or 300 mg day-1. “f 20s of the residual line (A) and the extrapolat “and 200 B 7Ds auc 25 litres ar“! a 25 O12:AL.1.1 Linear trapezoidal equation The area under a curve may be estimated by dividing it into sections and considering each section to be made up of a trapezium. The area of a trapezium can be obtained by finding the average length of the parallel sides and multiplying by the distance between them. Consider the graph shown in Fig. 6 and, in particular, the trapezium bounded by the points ty ty.» CP» Cp, The area of this trapezium will be (Cy + CPper? , % (yer = ty) cy Yb, Ce, oF CP nat by tel timeportions of the curve | When drug levels inthe body are declining exponentially it wll be more accurate to use the logarithmic form of the trapezoidal equation which is as | follows: ; (Cp, - CPnes AUC, 4) = x ty = tb bet af oe CP net For those interested in the derivation of the equation itis shown below in AI.1.3 Extrapolation | Using either the linear form of the trapezoidal equation, or a combination of fotime infinity | the linear and logarithmic forms of the equation itis possible to determine the area under the curve from time zero up to the time (t,) of the last measured concentration (Cp,). To measure the area under the curve from t, to infinity (+) the assumption is made that the drug concentration continues to decline exponentially until no more drug remains in the body. The relevant equation is as follows: Ce, AUCG, 44) = where k can be obtained from the terminal slope of a graph of In Cp versus time, (For those interested in the derivation of the equation itis shown below in section A1.3). to To estimate the final portion of the area under the curve it is necessa measure the terminal slope of a graph of In Cp versus time. There are be remembered that, b the slope of the fine, the values for concentration be converted into their natural log values. Alternatively, ordinary used and, after con sural log form, it can be plotte pe of graph paper is used, if the same line is d e same value for the termin:1.3. Derivation of | | | | | | | | This equation is a rearrangement of equation (2.8) ©) Least squares regression analysis of In Cp against time is another method for determining the terminal slope. The details for performing this type of regression can be found in the unit dealing with statistics or in most standard texts on statistics. Although this approach may, at first sight, appear to be completely objective, there is still a subjective element in deciding which data points are to be included for the purpose of the regression analysis. @Analternative method, which we will not consider further, isto perform compartmental modelling on the entire data set using a suitable non-linear regression analysis computer program, AUCK, + (aun D an LetU = -kt A and dU = -kdt “Ob, Therefore, dt = dU/-k Shae Substituting into equation (A1.1), : of F AUC ay = SE febu = Leds ats AUC,AUC, (AL3) When extrapoiatin: Oand equation (A1.3) simplifies to a) La AUCY, = = | Where Cp, is the final plasma concentration measured at time t,. Al4 Areg under the ist moment curve (in CP * fet CPoet? AlA.1 Linear | AUMC, _ SaSen ttt CPG a) trapezoidal equation : Al42 Log trapezoidal - ‘equation AUMCy 4) = : y | (Corer - Cry) | - oH (Coon)) =! (HfZ2) a. &C Se A143 Extrapoiation totime | aun, 2) = SR = infinityAL2 Muttizie iv. dosing Consider an intravenous bolus dose, D, given at regular intervals separated by time ‘t”. The manimum plasma concentration achieved with the first dose will be immediately following administration of the dose: D Comsat = ‘The minimum plasma concentration associated with the first dose will be immediately prior to administering the second dose, that is at time T following the administration of the first dose: where k is the apparent first order elimination rate constant ‘The maximum plasma level associated with the second dose will be equal to the sum of the concentration due to the second dose and that remaining from the first dose: D Dow | D ky 255 + = Bae CPmax2 = 5 v yire%) . Z ‘The minimum plasma level associated with the second dose will bit, a ered D CPmae = Fis e jon can be written in simpler form as: Da - eyRing ) in( FE kCp) = t+ constant But, when t= 0,Cp=0. Therefore, constant = Sutstituting for the integration constant gives: Ru) vo Multiplying both sides by “K’ and rearranging gives: Ria st _ xcp] In = -kxt ' Rise . ’ x ty ‘Taking antilogs of both sides gives: ee, Mh Rin : st Cp ‘ Rint Therefore,APPENDIX 3 | © Intimate mixing takes place between the hepatic portal blood and the hepatic arterial blood before drug partitions into sinusoids, S Modésis of hepatic Gecranme anes |. Calyantend any enka macro Underlying | essumpiions | * — Thereisno diffusional barrier between the drug in blood and the ° enzyme within the hepatocyte, that i, the rate of distribution is perfusion limited. * The rate of drug elimination is a function of the concentration of ‘unbound drug bathing the enzymes. Abbreviations common to both models: CLy = hepatic blood clearance ER extraction ratio Gh; unbound intrinsic clearance in the liver fu, unbound fraction of drug in blood Qe hepatic blood flow : p cme concentration of unbound drug inthe liver“ ” Ms : C, = concentration of drug in arterial blood C, = concentration of drug in venous blood A3.2 Well-siirred Additional assumptions are: mode! awell-stitred compart‘The minimum plasma concentration associated with the nth dose is therefore given by: CPminn = CPmasn |As the number of doses administered increases, the term eT will approach zero, so that the steady state maximum piasma concentration is given by: CPmanss = FS x val-e™) ‘and the minimum plasma concentration at steady state will be CPainss = CPmaxss®Therefore, CLy Cu, = Cly fay C, for most drugs Km >> fu, Cy sothat Cly = Rate of metabolism Therefore, & Cly = Clyfayc and ¢, Cl es GQ Substituting for = in equation (43.1) gives Qu: Chay Cly = Q&- Sa 2 a “CL fy (On rearrangement, is Venax fly C Km + fu, C, aassumptions are: ° that the liver is composed ofa large number of identical eylindsical tubes, arranged in parallel, with enzymes uniformly distributed in Parenchymal cells surrounding the cylinders and blood flows uunidirectionally along the cylinders * that at any point along the cylinder, distribution equilibrium exists between drug at the enzymatic site and in the cylinder, Figure 7 describes the profile of the drug concentration in blood in the Parallel tube model for hepatic clearance of drugs a I cy ; +———_ L ——____» . ’ oN, Figure7 Diagrammatic representation of the parallel tube model used describe hepatic drug clearance Additional abbreviations: L_ = total length of hepatocytes in the liver dx = length ofa single hepatocyte Cx = blood concentration at the hepatocyte ir ability to ise the drug, he total A hs, 8,Thersfore, L& Sie, ee Ge 7 MAT i gx Chili by Ot Ta > ae CL; fu, L ausice! =- TOs Chi fay Inc, = nc, = (cf) ate etae) 5 , but fy f1- =) “by, Cly = QER = Quill - Z}fice PEN D! Sg InCp (6)