CHAPTER l2
`
`INTEGRATION VVITH KJNEFICS
`
`187
`
`The therapeutic consequence of induction can be appreciated from the difference in
`the response—ii.me curves, shown in the bottom graph of Fig. 12-1. Respmise here is defined
`as the elevation in prothrombin time above a baseline value of 14 sec. The overall response,
`given by the area under the respoI1se—time curve after the single oral dose, is substantialiy
`reduced in the presence of rifampin. Consequently, one would expect under steady-state
`conditions that the dosage of warfarin must be increased in the presence of rifampin to
`maintain the same prothrombin time. The reason for the apparently poor correlation be-
`tween response and plasma warfarin concentration during the first 48 hr after warfarin
`administration, when response is increasing and concentration is falling, is discussed in
`Chap. 23, Turnover Concepts.
`_
`Rifampin is a known inducer of hepatic drug metabolism, and the data provided in Fig.
`12-1 are generally consistent with induction of warfarin metabolism by rifampin. However,
`there are problems with respect to the interpretation of these data, in addition to the above
`mentioned problem of relating warfarin concentration to response. Warfarin is marketed
`as a racematc. Its enantiomers have different anticoagulant potencies and different kinetic
`properties. Furthermore, the change in prothrombin time is a consequence of changes in
`several clotting factors. Racernates are commonly used today, instead of a pure enantiomer.
`One isomer may potentiate or inhibit the kinetics or dynamics of the other. As long as
`racemates are administered, lcinetic and dynamic data on the pure enantiorners, while
`helpful to define mechanisms involved, are of questionable value without corresponding
`data following the racemate as well. Clearly, chirality is a major issue in therapeutics.
`High Extraction Ratio. Induction of metabolism of a drug with a high hepatic extrac-
`tion ratio has lcinetic consequences very different from those of a drug with a low hepatic
`extraction ratio, as illustrated in Fig. 12-2. Pretreatment with the inducer pentobarbital
`appears to have little effect on the pharmacokineiics of alprenolol after its intravenous (i.v.)
`administration. Following oral administration, however, both the peak concentration (Cfim)
`and AUC are dramatically reduced, although there is little apparent change in the half—life.
`These observations, at first glance, appear to be inconsistent. Knowing that this drug is
`metabolized only in the liver and on calculating (from dose and AUC following i.v. admin-
`
`POID
`
`_|. 5
`
`N1#-
`
`
`
`PlasmaWarfann
`
`
`
`Concentration[mgiL)
`
`Prothrombin
`
`Fig. I2—l. The half—lj.fe of warfa-
`rin, a drug with a low extraction ratio.
`is shortened a s in-
`c —
`cles) as a single dose (1.5 mgficg} be-
`fore (black line) and while (colored
`circles and line} the inducer, rifarn—
`pin. is being administered as a 600-
`mg dose daily for 3 days prior to war-
`['an'n administration. The peak and
`duration of the elevation in the pro-
`thrombin time (response) are de-
`creased when rifampin is ccadmin-
`istered (lower graph) {1 mgL = 3.3
`DMJ. (Reproduced, with permission,
`from 0'Heilly, R.A.: Interaction of
`sodium warfarin and rifampin. Ann.
`Intern. Med., 5'I:337—‘340, 1974.}
`
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`CHAPTER 12
`
`istration) a clearance of 1.2 L/min in this individual, an explanation can be offered. Pen-
`tobarbital induces alprenolol metabolism, which manifests itself as a decrease in alprenolol
`oral bioavailability. The argument for this conclusion follows.
`The hepatic extraction ratio of alprenolol is high; its clearance approaches hepatic blood
`How, approximately 1.35 L/min, and its oral bioavailability (F), calculated by comparing the
`dose—corrected AUC after oral and i.v. administraiions, is 0.2.2. Given that the low bio-
`availahility is due solely to hepatic extraction, the hepatic extraction ratio (1 — FH) is 0.78.
`Bioavailability reflects the balance between perfusion, which forces drug through the organ,
`and enzymatic activity, which removes drug. After induction, which increases enzyme ac-
`tivity, oral bioavailability (based on comparison of AUC values) decreases to 0.06, almost a
`fourfold change, and hence the hepatic extraciion ratio increases to 0.94. Because clearance
`is perfusion rate-limited and because there is no evidence in humans that pentobarbital
`' alters hepatic blood flow, there is only a small increase in clearance. The increase in hepatic
`extraction ratio, and hence clearance, is only 20% (from 0.78 to 0.94). The lack of change
`in terminal half—life after induction also indicates that pentobarbital has no effect on the
`volume of distribution of alprenolol. Thus, induction of the metabolism of this drug, or any
`other drug with a high hepatic extraction ratio, has therapeutic implications when admin-
`istered orally, but not when given intravenously. A larger oral dose, or more frequent
`administration, is needed in the presence of the inducer to produce the same eftect, as-
`suming all activity resides with the drug.
`Alprenolol, like warfarin, is also administered as a racemate. With little difference in the
`kinetics of the isomers, the conclusions here for the mixture apply as well to each of the
`isomers. Indeed, if there are virtually no pharniacologic, toxicologic, or pharmacolcinetic
`differences between the isomers, a benefit in using the racemate is that it does not incur
`the often considerable cost of separating the isomers.
`
`Decreased Heputocellulur Activity
`
`Examples of drugs that inhibit the metabolism of other drugs are given in Chap. 17, In-
`teracting Drugs. Reduced metabolism can also be a consequence of hepatic disease (Chap.
`16), dietary deficiencies, and other conditions. Whatever the cause of decreased metabolic
`activity, the kinetic consequences depend on the hepatic extraction ratio of the drug.
`Low Extraction Ratio. The effect of decreasing hepatocellular activity for a drug of
`low hepatic extraction ratio is illustrated by data for chlorzoxazone and chlordiazepoxide.
`
`C) 2.;
`
`Induction of alprenolol
`Fig. 12-2.
`metabolism by pentobarbital treat-
`ment produces marked differences
`in the plasma concentration when
`t
`ru is
`'veno1-all
`200 mg), but
`hen g'ven i.v.
`mg). Alpren-
`o ol was administered before (black
`lines: ., i.\--.; O, oral) and 10 days
`into {colored lines: A, i.v.; A, oral)
`a pentobarbital regimen of 100 mg
`at bedtime (1 mg/L = 4.0 p.M)
`(From Alvan, (1.. Piafslry. K., Lind,
`M., and von Bahr, (3.: Effect of pen-
`tobarbital on the disposition of al-
`prenolol. Clin. Pharmacol. Ther.,
`22315-321, IQ77.)
`
`
`
`PlasmaAlprenololConcentration(mgfL)
`
`
`
`
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`INTEGRATEON WITH KII\iEl'iCI5
`
`139
`
`The concentration—time profile of the muscle relaxant chlorzoxazone in a subject after
`a T50-mg oral dose is very different from that seen 10 hr after a single 500-mg oral dose
`of disulfiram (Fig. 12-3). The mean clearance and half-life values were 3.3 ml/rnin/kg and
`1.2 hr in the absence and 0.5 ml/min/kg and 5.1 hr in the presence of disultiram, a selective
`inhibitor of oxidative metabolism. The changing concentration of the inhibitor (and its
`metabolites following the single 500-mg dose) and the limited time of sampling in the
`presence of the inhibitor preclude being highly quantitative. Nonetheless, the eflect of
`decreased hepatocellular activity is clear for a drug with 3. low extraction ratio; clearance
`decreases and half-life increases.
`-
`
`Another example is that of the anxiolytic drug chlordiazepoxide (Fig. 12-4). Its half—1ife
`is increased and its clearance is decreased in patients with hepatic cirrhosis. Oral bioavail—
`ability and volume of distribution (not shown) are unaffected.
`That ehlordiazepoxide has a low hepatic extraction ratio even in healthy subjects can be
`deduced from the data in the figure if one also lcnows that the drug is eliminated primarily
`
`Fig. 12—3. The plasma concentration-
`time profile of chlorzoxazone after a sin-
`gle 75(}—mg oral dose (A) is dramatically
`increased after disulfiram treatment (I).
`Disulfiram (500 mg orally) was given 10
`hr before the chlorzoxazone. The in-
`crease in half-life and decrease in clear-
`
`ance are expected for a low extraction
`ratio drug when metabolic activity is de-
`creased. (Redrawn from Kharasch,
`F..D., Thummel. ICE. Mhyre, L and
`Lillibridge, ].H.: Single-dose disulfiram
`inhibition of chlorzoxazone metabolism:
`
`A clinical probe for P450 21:11. Clin.
`Pharmaool. Ther. 53:643—650, 1993. He-
`produced with permission of C.V.
`Mosby.)
`
`Fig.12—4. Chlordiazepoxide'shalf-
`life is increased and total cleamnce is
`
`decreased in patienu with hepatic cir-
`rhosis compared to normal subjects.
`Mean (iSEM) and individual values
`are shown. {Redrawn from Sellers,
`E.M., Greenblatt, D.}., Giles, I-I.G.,
`Naranjo, C.A.. Kaplan,
`I-1., and Mac-
`Leod, S.M.: Clilordiazcpmdde and ox-
`azepain disposition in cirrhotics. Clin.
`Pharmacol. Ther., 26:240—246, 1979.
`Reproduced with permission of C.V.
`Mosby.)
`
`—.-L
`
`U1 <3
`
`-lb ID
`
`00 C)
`
`M {D
`
`cs8
`
`Cirrhosis
`
`Normal Cirrhosis
`
`
`
`
`
`GhlordiazepoxideClearance(ml/minikg)
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`3'--..
`3)
`E‘'11-’
`:
`.2
`":3L'I—‘
`I:
`as
`C.)
`3
`(.3
`cu
`::
`C)Mcu
`WC
`
`:C
`
`3E2.
`
`1:
`C.)
`[U
`EU)
`.
`
`ED
`
`
`
`
`
`ChlordiazepoxideHalf-life(hr)
`
`

`
`"I90
`
`INTEGRATION WITH KINETICS
`
`CHAPTER 12
`
`by hepatic metabolism, the blc-od—plasn1a concentration ratio is close to 1.0, and average
`hepatic blood How is 20 ml./min/kg. In subjects with normal hepatic function, the hepatic
`extraction ratio [CLH/QH = (0.55 ml/min/lcg)/(20 mL/min/l<g)] is then expected to be only
`about 0.03 or less.
`
`High Extraction Ratio. The kinetic consequences of inhibition of metabolism of a
`drug with a high hepatic extraction ratio are illustrated by the coaclrninistration of cirneti—
`dine and labetolol (Fig. 12—5). That labetolol is a drug of high hepatic extraction ratio is
`deduced from its clearance, 1.06 L/hr (estimated by dividing the i.v. dose by the corre-
`sponding AUC given in the article), approaching hepatic blood flow and from the knowl-
`edge that labetolol is eliminated almost exclusively by hepatic metabolism. The i.v. dose of
`labetolol is much smaller than the oral dose, because the drug is highly extracted in the
`liver, and hence subject to extensive first—pass hepatic loss, and because the pharmacologic
`activity primarily resides with the drug, rather than with its metabolites.
`There is a large increase in AUC for labetolol when administered orally, but not when
`given intravenously, in the presence of cimetidine. This observation is expected following
`inhibition of the elimination of a drug with a high hepatic extraction ratio. The lack of
`change in area Following i.v. administration reflects the minor decrease caused by cirneti-
`dine in the hepatic extraction ratio and hence in clearance. Evidently, blood flow continues
`to limit the hepatic elimination of labetolol even when inhibition occurs. This would not
`be so if the degree of inhibition were such as to reduce labetolol to a drug of low hepatic
`extraction ratio. The large increase in AUC following oral administration is a consequence
`of increased bioavailability; here the increment is about 56%, while only a minor decrease
`(20%) was seen in the hepatic extraction ratio. The therapeutic corollary of the lcinetic
`changes in the presence of cimetidine is heightened activity of labetolol when given orally,
`but not when given intravenously.
`
`Altered Blood Flow
`
`As presented in Chap. 1 1, changes in organ blood flow aliect clearance only when extraction
`ratio is high. This conclusion is based on the concept of a perfusion-rate limitation. It should
`be borne in mind, however, that effects secondary to an altered blood flow, particularly
`when decreased, may supersede perfusion considerations alone. For example, a decreased
`blood flow may produce anoxia, which in turn may aitect hepatocellular activity and hence
`the extraction ratio. The extraction ratio may also be altered by a decreased blood How
`
`AUC
`Oral
`
`I .V.
`
`Ct
`
`Fig. 12-5. Bioavailability increased,
`but clearance showed no significant
`(l\'.S.) change, when 6 healthy volun-
`teers were given labetolol either as a
`200—:ng dose orally or as a 0.5—n1gfl-:g
`dose i.v. before and on the fourth day
`of cirnetidine treatment (400 mg every
`6 hr). This conclusion is based on a sig-
`nificant change in AUG after oral, but
`not after i.v. administration. (Adapted
`from Daneshmend, T.I(., and Roberts,
`C._[.C.: The effects of enzyme induc-
`tion and enzyme inhibition on labeto-
`lol pharmacokinetics. Br. Clin. Phar-
`macol., 182393-400, 1984.)
`
`onCD
`
`0') G
`
`-32- (3
`
`IN.)
`
`CC:
`
`
`
`Percentchange
`
`I
`
`N) c:
`
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`INTEGRATION WITH KINETICS
`
`'I9l
`
`because every blood vessel in the organ may not provide the same exposure of the drug to
`hepatic parenchyrnal cells, and tire pattern of distributioir of blood flow within the elimi-
`nating organ may change. This alteration in the degree of shunting or bypassing of the
`parenchymal cells may occur in certain hepaiic diseases and under a variety of conditions.
`Good examples of the kinetic consequences of altered blood flow are hard to find. This
`is not because they are uncommon, but because a number of additional complications
`always seem to occur concurrently. For example, oonditions such as congestive cardiac
`failure, in which cardiac output is decreased, are often associated with increased third-
`spacing (build—up of fluid in intestinal spaces and body cavities), diminished hepatic and
`renal functions; and slowed distribution to the tissues. A decrease in hepatic blood flow,
`brought about by cirrhosis, chronically leads to portal hypertension and extralrepatic shunt-
`ing of portal blood. Thus, the kinetic consequences of altered blood flow are subsequently
`examined alone, with the realization that in therapeutic scenarios the effects of changes in
`more than one physiologic variable need to be considered.
`For this theoretical presentation, consider the two drugs given in Table 12.—3. Drug L
`is eliminated in both the liver and the kidneys; its major property is low extraction in both
`organs. Drug H has a high hepatic extraction ratio and is almost exclusively eliminated by
`the liver.
`
`Low Hepatic Extraction Ratio. Figure 12-6 shows the effect of a doubling of hepatic
`blood flow for the poorly cleared drug, drug L.Bec on
`ratio, altered blood flow has little or no effect on t e harmaco 'netics 0 this drug.
`Hepatic Ema dmmistrafion of a drug
`with a high hepatic extraction ratio, drug H, when hepatic blood flow is increased, are
`readily apparent. Not so apparent are the likely events that follow when drug H is given
`orally. Recall that F - Dose = CL - AUC or AUC = F - Dose/CL. Although the hallllife
`is shortened, clearance and oral bioavailability are increased simultaneously; oral bioa.vail—
`ability is elevated because drug in blood remains in the hepatic sinusoids for a shorter
`period of time with an increased blood flow, and therefore there is less chance of drug
`being eliminated. Accordingly, the result may be little or no change in AUC (last graph of
`Fig. 12-6). The outcome depends on whether or not the increase in bioavailability is exactly
`matched by that of clearance when blood flow is increased. The memory aids of Eqs. 2
`and 3 predict equal effects, in that the ratio of these equations (CL,/F” = CLW -firb) is
`independent of blood flow. Unfortunately, there is a lack of good quantitative information
`to be specific here.
`An example of a change in lcinetios with a change in blood flow is given with lidocaine
`in Fig. 12—7. Lidocaine is a drug with a high hepatic extraction ratio and whose clearance
`is perfusion rate limited. Here, as expected, the concurrent administration of either
`B-blocker, propranolol or metoprolol produces a decrease in the clearance of lidocaine.
`B—Blocl<ers reduce cardiac output and hepatic blood flow. The change in lidocaine clearance
`following propranolol administration is larger than that expected for the change in hepatic
`blood flow, suggesfing that one or more other mechanisms may also be operating.
`
`Table I 2-3. Plulrnltlcoklnollc Parameters of Tuna Hypall-Ieliclll Drugs
`VOLUME OF
`FRACTION
`DISTRFBUTION
`eccssrto
`[u
`UNCHANGED
`
`EXTRACTION R.-mo
`-T-T
`HEPATIC
`RENAL
`
`BIOAVAILABILIH“
`
`CLEARANCE”
`[L/hrl
`
`26
`0.97
`430
`_0.05
`"Bioovoiiohi|'IJy is fully cocounled For by lirst-puss rneiooolism in the liver.
`f'Clec:rcnce is based on mecisuremenlol‘ drug in blood.
`
`C)
`77
`
`0.60
`0.05
`
`0.03
`0.95
`
`0.05
`0.00
`
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`FNTEGRATION WITH KINETECS
`
`CHAPTER T2
`
`Altered Active Tubular Secretion
`
`Figure 12-8 shows the effect of inhibiting the renal tubular secretion of amoxicillin by
`probenecid. An increased AUC of amoxicillin is obvious; it reflects a decrease in clearance.
`The prolongation of elimination half~life is also due primarily to reduced clearance; the
`volume of distribution (CL/Jlc) is changed relatively little, indicating that probenecid does
`not affect the distribution of arnoxicillin. The inhibition of renal excretion of this penicillin
`by probenecid becomes apparent when this pathway is isolated. Renal clearance, that is,
`the excretion rate relative to the plasma concentration, is clearly reduced by probenecid.
`The substantial renal excretion of amoxicillin explains why a reduced renal clearance has
`such a pronounced effect on total clearance.
`The decrease in renal clearance occurs by inhibition of the tubular secretory mechanism
`for amoxicillin, a drug that is virtually unbound to plasma proteins. The degree of inhibition
`of this process is masked by the contribution of filtration at the glomemlus. If secretion is
`
`intravenous Dose
`
`Oral Dose
`
`p''—'-.
`
`5.C3:
`
`EI
`
`:
`.91-‘
`E-II‘-5
`1:G)
`L‘:
`L:
`C)
`(.7
`‘:3::1L
`c:
`C3
`2I
`
`Z‘
`
`0.0001
`
`Hours
`
`Fig. 12-6. Increased blood fl ow to the liver has veiy little e£I'ect on the time course of Drug L, a poorly extracted
`drug, a.f‘t(-:1‘ either an oral or i,v. 15—mg close but has 8. pronoimced effect on Drug H, a highly cleared drug,
`following single i.v. (15~mg) and oral (300-mg) doses. Altered condition (—-~-); normal condition If
`). The
`absorption rate constant of both drugs is L-1 hr. See Table 12-3 for other pharmacokinetic properties of these
`two drugs.
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`INTEGRATION WiTH KINETICS
`
`193
`
`completely blocked, renal clearance of this polar antibiotic is expected to have a lower limit
`offu - GFR because it is not reabsorbed in the tubule;
`
`Altered Plasma Protein Binding
`
`Knowledge of conditions in which the binding to plasma proteins is altered is critical to
`plasma drug concentration rnoriitoring (Chap. 18). Vi/hen activities, desired and undesired,
`relate to the unbound concentration, changes in binding directly atfect the interpretation
`of total concentration data. This problem applies to drugs of both low and high extraction.
`Wliether or not the altered binding affects the unbound plasma concentration, and there-
`fore the concentration at the active site is therapeutically important. These aspects are now
`addressed in turn.
`
`3_~.:
`‘:2_:
`:3"|I—7
`
`8C
`E’to
`33
`C.)
`O}
`.L:.EUr_'>
`3
`:9_I
`
`53 or.-
`
`E3 4:-
`
`Propranolol
`
`Fig. 12-7. The clearance of lido-
`caine following a 4—min iv. infusion
`(3 mg/kg) is reduced during 1neto—
`prolol
`(50 mg) or propranolol (40
`mg] administration (every 6 hr be-
`ginning 24: hr before the test dose
`and continuing For 8 hr tliereatter).
`These drugs decrease cardiac output
`and hepatic blood flow, the primary
`mechanism by which the clearance
`of lidoeaine is thought to be reduced.
`(1 mg/L = 4.3 plvl) (Adapted from
`Conrad, K.A., Byers, }.‘.\rI., Finley,
`RR, and Burnhan-1, L.: Lidocainc
`elimination: Effects of metoprolol
`and of propranolol. Cljn. Pharmacol.
`Ther., 33;133_133, 1933.)
`
`_L (3
`
`
`
`PlasmaAmoxiciliin
`
`
`
`Concentration(mgiL)
`
`Plus
`Probenecid
`
`
`
`AmnxicillinF{ena1
`
`
`
`Clearance(mumin)
`
`0.1
`
`0
`
`I
`2
`
`1
`4
`
`I
`6
`
`I
`3
`
`Fig. 12-8. The plasma concentration (on left), and hence the AUC, tor amoxiciilin is increased when 500 mg
`are administered orally in solution to fasting subjects in the presence (colored curve) and absence (black curve)
`of probcnecid (1 g, 12 hr and then 1 hr before the antibiotic). The effect is due to probenccid decreasing the
`renal clearance of amoxicillin (on right), the major component of total clearance (1 mg/L = 2,7 |.I.l\-'1} (Data from
`Stanifortli, D.I-1., Jackson, D., Clarke, H.I.., and Horton, R.: Amoxicillin/clavulanic acid: The efiect ofprobenecicl.
`]. Anrirnicrob. Cliernothen. 12:2'?'3—275, 1983.}
`
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`194
`
`INTEGRATKDN Will-i KINETICS
`
`CHAPTER I2
`
`Low Extraction Ratio. Changes in the therapeutic window of phenytoin as a function
`of serum creatinine concentration, an index of renal function, is shown in Fig. l2~9. The
`higher the creatinine concentration, the lower is the renal function. The window falls
`because fu, normally about 0.1, increases to about 0.25 to 0.3 in patients with severe renal
`function impairment.
`For example, given that the unbound concentration required to produce a given re-
`sponse in the presence of renal disease is the same as that in the absence, it follows that
`
`Fa-C=t'b'-C’
`
`4
`
`where fit’ and C’ ’ are the unbound fraction and total drug concentration in the presence
`of the disease, respectively. On rearrangement
`'
`
`Fu
`
`C!
`
`Concentrations of 10 and 20 mg/L in normal conditions thus become equivalent to 4 and
`8 mg/L when fu andfa’ are 0.1 and 0.25, respectively.
`Phenytoin is a low extraction
`eliminated by hepatic metabolism. Consequently,
`elimination is related to its unbound concentration (Chap. 11). Total clearance (fu - CLu)
`increases in renal disease, but there is no requirement for dosing rate adjustment because
`unbound clearance, the proportionality constant between rate of input and unbound con-
`centration at steady state, is not affected by the binding change.
`Iiigh Extraction Ratio. Figure 12-10 shows how blood clearance, volume of distri-
`bution, and half-life of propranolol vary with the Eraction unbound in six healthy male.
`volunteers. Clearance appears to be independent of protein binding. The volume of dis-
`tribution (blood) and half—life both increase with an increase in This is the behavior
`expected for a drug with a large volume of distribution and for which elimination is per-
`fusion rate—limited. The drug is primarily eliminated by hepatic metabolism, and the met-
`
`20
`
`18
`
`16
`
`14
`
`12
`
`10
`
`
`
`PlasmaPhenytoinConcentration(mg/L}
`
`
`
`
`
`Fig. 12—9. The therapeutic range of
`phenytoin based on total plasma concen-
`tration decreases with the degree of renal
`Function impairment, as measured by se-
`rum creatinine, from the usual values of
`ID to 20 mg/L. This decrease is a conse-
`quence of reduced binding, which is re-
`lated to the severity of the renal disease (1
`mg/L = 4.0 y.zM). (Iiedrawn from Reiden—
`berg, M.M., and Affrime, M.: Influence of
`disease on binding of drugs to plasma pro-
`teins. Ann. N.Y. Acad. Sci., 226:1l5—126,
`1973.)
`
`1
`
`50
`
`"I"
`
`100
`
`‘I50
`
`"I
`
`200
`
`Serum Creatinine Concentration (mglL)
`
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`
`INTEGRATION WITH KINETICS
`
`I95
`
`abolic (blood) clearance approaches hepatic blood flow (1.35 L/min on average). The in-
`crease in volume of distribution with fu, is anticipated; as is the increase in half—]ife.
`With the increase in fix and no change in clearance, there must be a corresponding
`int‘
`decrease in unbound clearance, since CL,, = fab - CL.
`This means that the unbound
`concentration under constant—rate i.v. infusion conditions is increased when binding is
`decreased and the converse; an effect with potentially important therapeutic consequences.
`An alternative view of this situation is to remember that when clearance approaches blood
`flow in the eliminating organ, total steady-state concentration is not expected to change
`with altered plasma binding. An increase in fu thereby raises the unbound concentration
`and the drug’s effects. Although there are many drugs with a high hepatic extraction ratio,
`they are fortunately seldom given chronically by the parenteral route under conditions in
`which binding is altered.
`The oral bioavailability of a drug with a high extraction ratio is expected to decrease
`with an increase in fu, as seen from Eq. 17 0? Chap. 11, when CLM is much greater than
`Here CLu/F = CLW. The memory aid model of Chap. 11 predicts little or no change
`in the steady-state unbound concentration or the therapeutic response after oral adminis-
`tration, because CLM is unchanged.
`Small Voluine of Distribution. The consequence of altering binding to plasma pro-
`teins is illustrated by clofibrate. The half—life of clofibric acid (the active material formed
`by hydIolysis of the administered ethyl ester, clofibrate} shortens from the usual 16.5 hi-
`to 8.7 hr in patients with the nephrotic syndrome (Table 12-4). It is tempting to conclude
`that metabolism (only 6% of clofibiic acid is excreted unchanged) is induced and that
`dosage requirements need to be increased in these patients. From a pharrnacokinetic point
`of view, these conclusions are incorrect, as the following shows.
`
`
`
`
`
`Half-LifeVolumeofBloodClearance
`
`12
`
`1
`
`1.0
`
`
`
`Distribution(L)(L/mm)
`
`A
`
`Fig. 12-10. The clearance of propranolol
`(Graph A), based on its concentration in blood,
`does not appear to correlate with the fraction
`unbound in blood of six healthy male volunteers
`after intravenous administration of 20 mg. On
`the other hand, the volume of distribution
`(graph B) and the half—liFe (graph G} are ob-
`served to increase with an increase in the frac-
`tion unbound. This kinetic behavior is antici-
`
`pated for a drug, such as propranolol, that is
`highly extracted in the liver. Clearance here is
`perfusion rate-limited. Binding to plasma pro-
`teins does not influence clearance but does af-
`fect the volume of distribution and, therefore,
`the half-life. The lines are the best fits by linear
`regression.
`(1 mg/L = 3.9 |.1M) (Data from
`Evans, G.H., and Shand, D.G.: Disposition of
`propranolol. VI: Independent variation in
`steady-state circulating drug concentrations and
`half-life as a result of plasma drug binding in
`man. Clin. Pharmacol. Ther., 14:494—500, 1973.
`Reproduced with pcrrnission of C.V. Mosby.)
`
`0.07
`
`0.08
`
`0.09
`
`0.10
`
`0.11
`
`Fraction Unbound in Blood
`
`141 of 156
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`
`INTEGRATION wam KJNETJCS
`
`CHAPTER 1 2
`
`In the nephrotic syndrome, there is an extensive loss of plasma proteins into the urine,
`which results in a twofold drop in serum albumin, as shown in Table 10—7'. The influence
`of this drop in serum albumin onfu. can be estimated from rearrangement of Eq. 18 (Chap.
`10). The normal serum albumin concentration reported is 4.3 g/dL and for clofibric acid
`fu is 0.03. Given that fitp, the fraction of available binding sites unoccupied, is equal to 1,
`the value of K0 is 7.5 dL/g. At a serum albumin concentration of 2.3 g/dL, the calculated
`fraction unbound in nephrotic patients is then
`
`I
`’“=T:r7.“r<“23 = 0.055
`
`‘ Clofibric acid has a low extraction ratio in that its clearance (calculated from k - V) is 0.32
`L/hr in healthy subjects, a value much smaller than hepatic blood flow, 81 L/hr. Although
`one might argue that blood clearance is much larger than plasma clearance (also C/Cb >
`1), this is impossible. Virtually all drug in the body is bound to albumin (V = 0.11 L/kg).
`Thus, plasma drug concentration can only be greater than blood drug concentration by a
`factor of 1.7 [1/(1 — hematocrit); see Appendix I—F.
`With clofibric acid being a low extraction ratio drug, clearance is expected to increase
`in nephrotic patients. The value of unbound clearance, CL/fie, is 10.7 L/hr in healthy
`subjects. If one assumes the same unbound clearance in nephrotic patients, then clearance,
`fit - CLu, in this group is 0.59 L/hr.
`_
`The volume of distribution of clofibric acid, given in the footnote to Table 12—4, is 7.7
`L/70 kg. This value depends little on changes in plasma protein binding. This is seen from
`the relationship between V and fit for a drug with a small volume of distribution (Eq. 25,
`Chap. 10), namely,
`
`V = 7.5 + Constunt- FU
`
`With an apparent volume of 7.7 L, the constant is 6.7. Iffu is increased to 0.055, then the
`apparent volume becomes 7.9 L. The volume unbound (V/fu), however, decreases from
`257 to 143 L. The calculated half-life (0.693 - V/CL or 0.693 - Va/CL-u) in the nephrotic
`patients is then about 9.3 hr, a value very close to that observed, 8.7 hr.
`The two questions originally posed are now answered. The half—life is shortened in the
`nephrotic patients because of decreased binding to albumin-, metabolism was not induced.
`Unbound clearance was not changed, and therefore no change ‘in the usual dosing rate of
`1.5 to 2.0 g/day is needed in nephrotic patients to produce the same average unbound
`concentration in plasma, as achieved in patients with normal serum albumin. A shorter
`
`llennl Funclien Measures, Serum Albumin, Daily Protein Excrelion,
`‘fable ‘I 2-4.
`and Half-Life of llle Aeliva Form of Clofflarule, Clolilarie Acid, in Pufionis Wifh
`and Without l'l|e lllepllrelic Syndrome“
`SERUM
`CREATININE
`CREATll\l.'NE
`CLEARANCE
`lmg/dill’
`{ml/mini
`
`SERUM
`NBUMIN
`lg/dL,I
`
`CLOFIBRIC ACID
`HALFUFE
`lhrl
`
`PROTEIN
`EXCREHON
`[g/day]
`
`Nephrofc group
`iN=5}
`Confrol group
`[N = 8]‘
`
`l.3iO.l
`
`lOOi2-41
`
`2.3-$0.5
`
`8.7i3.5
`
`l3il2
`
`L2 i 0.2
`
`98 i 20
`
`4.4 i 0.4
`
`16.5 i 4.7
`
`O
`
`“From Goldberg, A.P., Sl-nerrard. D,J., Hoes, LB., and Brunzell,_I.D..' Conlrol of clolibrclle loxicfly in uremic hypc.1IigiycerI'dernia. Ciin. ."'hr:Irr.'1c:cc:l. Then,
`2 l:3 l 7-325, l977.
`bone mg/or = as pm
`l L/l<g,rl1elracrIrcn unbound in plasma is 0,03, and the fraction excreted unchanged
`"In hec|!hx_.- subjects, Ihe volume of dish.‘-biilion of clolfblic acid is O. I
`is 0.00. [Data from Benet, L,Z., and Wiiliams R.L: Appendix II. in The Fhormocologic Bests o.'TI1ercipeutics. 3ll'l ed. Edited byA.G_ Gllmon, T.W_ Roll,
`A5. Miss, and P. Taylor. New York. Mucmi.'|-an.
`l"-}C‘3.|
`
`142 of 156
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`CFAD V. UPENN
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`
`CHAPTER12
`
`INTEGRATION WiTH KINETICS
`
`197
`
`Table I 2-5. Anlitipaiecl Effects 0! Allerulions in Selected Physiologic Variables
`on Various Purumelars and Observations for Drugs Eliminuleal solely by Ilsa liver
`PHYEHOLCGIC VARIABLE ALTE RED
`
`PARAMETERS
`OR
`OBSERVATZONS
`
`iNcIéEAsED
`ENZYME
`ACTNtTY‘”
`
`INHEBITION
`OF
`ME TABOIJSM
`
`DECREASED
`BLOOD
`FiOW
`
`INCREASED
`
`‘¥+§"i';%??.is
`I-I-u—.:...
`
`Holt-life
`AUC {blood}
`Btoovoilobilily-..q\D L
`AUC {blood}
`
`Holt-life
`AUC {blood}
`Bioovoilobilify
`AUC [blood]
`
`Low Hepolic Exrroction Rotio Drug
`T
`
`C-1‘
`
`r
`we
`‘
`C)
`pcliic Extraction Rollo Drug ""'
`‘-9’
`1‘?
`i—}
`:
`:
`
`H
`
`e
`s°~‘;,°
`' ?lo0
`
`4—F
`
`wx
`1°"
`
`ADMENISTRATION
`
`lnirovenous
`
`Orol
`
`lmro venous
`
`"V> 50lForalldrugs.
`
`‘Enzyme ocliviry is increases iayorie of several mechanisms, such as enzyme cclivotien, 'nduc:n‘on, or increased ovoiicbilfry of coFuc:ors, if rule-Iimillng.
`‘T increased; l clecrensee; vr Iillle or no change.
`dine decrease in blocivcinobiliry is ossumed to be equally molched by cu decrease ir'- clcoroncc.
`
`dosing interval (and correspondingly smaller maintenance dose) might be considered be-
`cause of the shortened half-life.
`
`The combinations of conditions and scenarios in drug therapy are multitudinous. This
`chapter has presented approaches and examples toward integrating kinetic principles and
`physiologic concepts. To complete this integration, Table 12-5 summarizes the effects
`expected from increased enzyme activity, inhibition oi metabolism, decreased blood flow,
`and increasedfir in blood for a drug elirninated exclusively in the liver. Conditions involving
`drugs of both low and high extraction ratios are considered. The expectations are similar
`for a drug eliminated only by the kidneys; however, increased active tubular secretion rather
`than increased enzyme activity applies. Also, oral bioavailability of a drug highly extracted
`in the lddneys is unaffected by changes in the physiologic variables considered here.
`
`STUDY PROBLEMS
`
`(Answers to Study Problems are in Appendix II.)
`
`1. List 10 examples of physiologic variables that alter pharmacokinetic parameter values.
`2. Complete Table 12-6 below to show tendencies by marking: T for increase,
`~l« for
`decrease, and (—> for little or no change in the empty spaces. The drug is only eliminated
`in the liver, and its volume of distribution is greater than 100 L. There is no change
`in intrinsic clearance.
`
`'I'uI:Ie I 2-6.
`HE PATIC
`HEPFHC
`EXTRACTION
`BLOOD
`RATIO
`FLOW
`
`FSEACTION
`IN BlOOD
`UNBOLIND
`
`FRACT