Pharmacokinetics of losartan, an angiotensin
`II receptor antagonist,
`and its active
`metabolite EXP3 174 in humans
`
`its active car-
`and
`potassium
`losartan
`antagonist
`receptor
`II
`the angiotensin
`of
`The pharmacokinetics
`in 18 healthy male subjects after administration
`of
`EXP3174
`were characterized
`boxylic
`acid metabolite
`intravenous
`EXP3174,
`and oral
`losartan.
`In
`these subjects,
`the average
`plasma
`intravenous
`losartan,
`clearance
`losartan was 610 ml/min,
`and
`the volume
`of distribution
`was 34 L. Renal
`clearance
`(70
`of
`ml/min)
`accounted
`for 12% of plasma clearance.
`Terminal
`half-life
`was 2.1 hours.
`In contrast,
`the aver-
`age plasma
`clearance of EXP3174
`was 47 ml/min,
`and
`its volume
`of distribution
`was 10 L. Renal clear-
`ance was 26 ml/min,
`which
`accounted
`for 55% of plasma
`clearance;
`terminal
`half-life
`was 6.3 hours.
`After
`oral administration
`of losartan,
`peak concentrations
`of losartan were
`reached
`in 1 hour. Peak con-
`centrations
`of EXP3174
`were
`reached
`in 3Yz hours.
`The area under
`the plasma
`concentration-time
`curve of EXP3174
`was about
`four
`times
`that of losartan.
`The oral bioavailability
`of losartan
`tablets was
`33%. The
`low bioavailability
`was mainly
`attributable
`to first-pass metabolism.
`After
`intravenous
`or oral
`administration
`of losartan
`the conversion
`of losartan
`to the metabolite
`EXI’3174
`was 14%.
`(CLIN
`PHAR-
`1995:58:641-9.)
`MACOL
`THER
`
`MD, PhD,
`Lo, PhD, Michael R Goldberg,
`Man-Wai
`I. Furtek,
`Lu, BS, Christine
`B. McCrea,
`PharmD,
`Hannah
`Jacqueline
`Thorir
`D. Bjornsson, MD, PhD West Point and Philadelphia, Pa.
`
`BS, and
`
`One of the most important regulators of blood pres-
`sure is the renin-angiotensin system.’ Interruption of
`this hormonal system has provided a means for con-
`trolling hypertension, as shown by the efficacy of the
`angiotensin converting enzyme (ACE) inhibitors cap-
`topri12 and enalapril.” However,
`it is becoming
`in-
`creasingly clear that both ACE and renin” have other
`substrates, some outside the renin-angiotensin system.
`For example, ACE also cleaves the vasodepressor and
`inflammatory
`nonapeptide bradykinin
`into
`inactive
`fragments. A side effect
`that can be associated with
`ACE inhibitors
`is a dry cough, possibly the result of
`bradykinin potentiation,’
`thus showing the need for a
`more specific mechanism
`for the treatment of hyper-
`tension.
`
`R2
`
`RI
`
`CH,OH
`
`COOH
`
`R2
`
`K
`
`H
`
`LCSartZIIl
`potassium
`EXP3174
`
`and Clinical
`of Drug Metabolism
`the Departments
`From
`Laboratories,
`West Point,
`and
`ogy. Merck
`Research
`of Clinical
`Pharmacology,
`Department
`of Medicine,
`ferson
`University,
`Philadelphia.
`Received
`for publication
`May
`9, 1995; accepted
`Reprint
`requests:
`Man-Wai
`Lo, PhD, Department
`lism, WP28-18,
`Merck
`Research
`Laboratories,
`19486.
`0 1995 by Mosby-Year
`Copyright
`0009.9236/95/$5.00
`+ 0
`13/l/67515
`
`Book.
`
`Inc.
`
`Structures of losartan potassium and EXP3 174.
`
`Pharmacol-
`the Division
`Thomas
`Jef-
`
`3, 1995.
`July
`of Drug Metabo-
`West
`Point.
`PA
`
`Recently a new class of drugs has been developed
`to inhibit
`the action of angiotensin
`II at its receptor.
`Losartan potassium
`(2-butyl-4-chloro-
`I-[p-(0- lH-tet-
`razol-5ylphenyl)benzyl]imidazole-5-methanol
`mono-
`potassium salt; see Structure),
`is a highly selective
`641
`
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`
`t
`mux
`(hr)
`50 mg oral dose of losartan
`1
`1.8
`649
`0.5
`3.6
`2
`250
`0.5
`2.3
`3
`178
`2.0
`4
`2.3
`89
`1.3
`3.7
`5
`416
`0.8
`2.3
`6
`733
`1.3
`2.3
`7
`49
`1.3
`2.0
`8
`76
`1.8
`9
`1.8
`195
`1.3
`2.2
`10
`317
`0.8
`1.7
`11
`235
`0.5
`1.5
`12
`370
`0.5
`2.1$
`Mean
`1.0
`296
`SD
`0.5$
`217
`0.5
`dose of losartan
`-
`-
`
`-
`-
`
`20 mg intravenous
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`Mean
`SD
`
`-
`
`-
`-
`-
`-
`-
`
`642
`
`Lo et al.
`
`CLINICAL
`
`P HARMACOLOGY
`
`& THERAPEUTICS
`DECEMBER 1995
`
`Table I. Summary pharmacokinetics of losartan and EXP3174 after a 50 mg losartan tablet and a single 20-minute
`intravenous infusion of 20 mg losartan in 12 healthy male subjects in study l*
`Losartan
`
`Subject
`No.
`
`tv2
`fhr)
`
`AUC
`hrlml)f
`
`(ng
`
`CL
`(mlimin)
`
`CL,
`(mllmin)
`
`in
`
`%Dose
`urine
`
`Oral F
`f%)
`
`727
`586
`355
`307
`766
`690
`184
`282
`484
`608
`254
`464
`476
`200
`
`436
`630
`462
`489
`716
`465
`610
`549
`485
`647
`417
`557
`
`539
`95
`
`-
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`763.8
`529.3
`721.4
`681.1
`465.5
`717.3
`546.2
`607.5
`687.3
`514.9
`799.1
`598.1
`
`636.0
`107.4
`
`69.9
`48.5
`84.2
`89.0
`62.6
`60.6
`55.2
`56.7
`103.0
`43.7
`89.8
`101.3
`72.0
`20.6
`
`83.1
`38.6
`95.0
`89.8
`54.2
`61.9
`73.2
`58.9
`104.6
`44.7
`73.8
`88.0
`
`72.1
`20.8
`
`39.9
`21.2
`24.0
`31.8
`31.0
`28.5
`16.0
`22.1
`65.9
`19.0
`20.8
`20.2
`
`28.4
`13.6
`
`6.6
`3.5
`4.0
`3.3
`5.7
`4.8
`1.3
`2.3
`6.5
`3.4
`2.8
`6.1
`4.2
`1.7
`
`10.9
`7.9
`13.9
`13.6
`12.1
`9.8
`13.9
`10.3
`15.1
`9.4
`10.9
`16.0
`
`12.0
`2.5
`
`2.4
`1.6
`1.4
`2.1
`2.9
`2.1
`2.0
`1.7
`3.9
`1.7
`1.1
`1.4
`1.84
`0.6$
`
`-
`
`-
`
`-
`
`-
`-
`-
`-
`
`66.6
`37.2
`30.7
`25.1
`42.8
`59.4
`12.1
`20.6
`39.9
`37.5
`24.4
`33.3
`
`35.89
`15.5
`
`-
`
`-
`
`volume of distr-
`
`time
`t,,,,
`C maxi Peak plasma concentration;
`bution; CL, plasma clearance; F, bioavailability.
`dose were 49.1 mg and 19.7 mg as losartan potassium,
`*The assayed potencies of the losatan
`tablet and the mean intravenous
`tData normalized
`to 20.0 mg intravenous
`and 50.0 mg oral dose on the basis of assayed potency.
`*Harmonic mean and pseudo standard deviation.
`§Geometric mean is 32.6%.
`
`to reach C,,,;
`
`tl/Z, half-life; AUC, area under
`
`the plasma concentration-time
`
`curve; V,,, steady-state
`
`respectively.
`
`AT,-subtype, non-peptide, orally active angiotensin II
`receptor antagonist.6 It has been shown to be active in
`animal models of hypertension6 and to be antihyper-
`tensive in humans7-” This mechanism would be ex-
`pected to be free of the actions of ACE inhibitors
`that
`are due to bradykinin potentiation,
`such as cough,
`while maintaining clinical efficacy and general toler-
`ability.
`Characterization of activity of losartan in animals
`revealed
`that
`the 5-carboxylic
`acid of
`losartan,
`EXP3174 (Structure), is an active metabolite
`that con-
`tributes to the overall
`in vivo activity of losartan in
`animals’.’ and humans.12 However,
`losartan is not a
`
`pro-drug because losartan itself is a potent angiotensin
`II antagonist.
`In vitro human microsomal
`investiga-
`tions have suggested that the conversion of losartan to
`EXP3174 is catalyzed by two cytochrome P450 sub-
`families: CYP3A4 and CYP2C9.13 Pharmacokinetics
`of losartan in humans after oral administration have
`been described.‘4*‘5
`To understand the relationship between the pharma-
`cokinetics of losartan and its clinical activity, it is nec-
`essary to investigate its disposition after oral and intra-
`venous administrations and to examine the disposition
`of the active metabolite.
`In this article, the pharmaco-
`kinetics of losartan after both oral and intravenous ad-
`
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`EXP3 I74
`
`2174
`2333
`2197
`1872
`1370
`1414
`1694
`1316
`2187
`3187
`1751
`1487
`
`1915
`538
`
`464
`1241
`766
`623
`693
`500
`718
`579
`934
`1279
`572
`562
`
`744
`272
`
`387
`271
`2.58
`198
`189
`189
`241
`154
`249
`391
`249
`217
`
`249
`74
`
`4s
`137
`x9
`61
`57
`48
`71
`45
`99
`125
`72
`69
`
`76
`30
`
`2.0
`4.0
`6.0
`4.0
`3.0
`4.0
`4.0
`7.0
`6.0
`3.0
`2.0
`4.0
`
`4.1
`1.6
`
`4.0
`4.0
`4.0
`4.0
`4.0
`4.0
`4.0
`6.0
`4.0
`4.0
`4.0
`4.0
`
`4.2
`0.6
`
`3.9
`7.6
`8.4
`6.5
`14.0
`5.1
`8.7
`4.9
`6.0
`8.4
`8.9
`4.5
`
`6.4:
`2.3$
`
`3.2
`4.4
`3.6
`4.5
`6.5
`4.9
`6.3
`5.4
`3.7
`10.3
`4.1
`3.6
`
`4.6$
`1.33
`
`21.3
`27.4
`32.5
`21.9
`23.1
`19.3
`18.4
`25.8
`37.0
`18.0
`28.7
`37.7
`
`25.9
`6.9
`
`22.4
`24.4
`29.5
`32.7
`27.2
`33.0
`20.1
`26.7
`3X.2
`19.6
`34.5
`32.1
`
`28.4
`6.0
`
`5.9
`7.9
`8.8
`5.2
`3.7
`3.6
`3.7
`4.3
`10.0
`7.2
`6.2
`7.0
`
`6.1
`2.1
`
`3.5
`9.8
`7.6
`6.4
`5.7
`5.2
`4.3
`4.8
`11.7
`7.3
`6.2
`5.8
`
`6.5
`2.3
`
`(study 1) is described. In addition, be-
`ministrations
`cause EXP3 174 contributes to the pharmacodynamics
`of losartan, the metabolite’s pharmacokinetics after in-
`travenous administration and the extent of conversion
`of oral and intravenous losartan to EXP3174 (study 2)
`was studied. The in vitro blood-to-plasma concentra-
`tion distribution
`ratios of losartan and EXP3 174 were
`also determined.
`
`AND METHODS
`
`MATERIAL
`Study design
`randomized,
`Study 1. The study was a two-period,
`open crossover study to investigate
`the intravenous
`disposition and oral bioavailability of losartan tablets.
`On two occasions after an overnight
`fast, 12 healthy
`male subjects (age range, 21 to 36 years; mean weight,
`
`Lo et al. 643
`
`75.6 kg) were given losartan potassium salt either as a
`single 50 mg tablet orally or as a 20 mg, 20-minute,
`constant-rate intravenous infusion in saline solution. A
`minimum 7-day washout period separated the treat-
`ments.
`tubes
`Blood samples were collected in heparinized
`at 0, 15, 30, and 45 minutes and at 1, 1 I/?, 1 r/2, 1 VI, 2,
`3, 4, 5. 6, 7, 8, 10, 12, 18, 24, 30, and 36 hours after
`the administration of oral losartan, as well as at 0, 5,
`10, 15, 20, 23, 26, 30, 45, 60, and 90 minutes and at 2,
`3, 4, 5, 6, 7, 8, 10, 12, 18, 24, and 30 hours after ini-
`tiation of administration of intravenous losartan. Total
`urine voided
`for 48 hours after drug administration
`was collected at the following
`intervals: predose and
`at 0 to 3. 3 to 6. 6 to 12, 12 to 24, 24 to 36, and 36 to
`48 hours.
`Study 2. This was an open, three-period crossover
`study in six different healthy male subjects (age range,
`22 to 30 years; mean weight, 78.6 kg) to study the
`conversion of losartan to EXP3 174, the intravenous
`disposition of losartan and EXP3 174, and the oral bio-
`availability of losartan solution. All doses were admin-
`istered after an overnight
`fast. A solution of losartan
`(t4C-radiolabeled) was administered
`in a randomized
`sequence in the first and third periods as a single 100
`mg oral dose and as a single 30 mg, 20-minute, con-
`stant-rate intravenous infusion
`in saline solution. Dur-
`ing the second treatment period. EXP3 174 was admin-
`istered as a single 20 mg, 20-minute, constant-rate
`intravenous
`infusion
`in saline solution. Each period
`was separated by at least 7 days. Blood samples were
`collected
`in heparinized
`tubes at 0. 15, 30, and 45
`minutes and at 1, 1 l/r, 2, 3, 4, 6, 8, 12, 18, 24. 30, 36.
`and 48 hours after the administration of oral losartan;
`at 0, 10, 20, and 30 minutes and at 1, 1’/2. 2, 3, 4, 6, 8.
`12, 18, 24, 30, 36, and 48 hours after initiation of the
`administration of intravenous
`losartan; and at 0. 10,
`and 20 minutes and at 1, 2, 4, 6, 9, 12, 18. 24, 30, and
`36 hours after the initiation of the administration of in-
`travenous EXP3174. Total urine voided for 96 hours
`after the losartan doses was collected at the following
`intervals: predose and 0 to 2, 2 to 4, 4 to 6. 6 to 8, 8 to
`12, 12 to 18, 18 to 24, 24 to 36, 36 to 48, 48 to 72,
`and 72 to 96 hours. For intravenous EXP3174.
`total
`urine was collected for 48 hours at the following
`inter-
`vals: predose and 0 to 3, 3 to 6, 6 to 12, 12 to 24. 24
`to 36, and 36 to 48 hours.
`
`Sample assays
`for lo-
`Plasma and urine samples were analyzed
`sartan (as potassium salt) and EXP3174 (as free acid)
`simultaneously
`by a validated HPLC assay with
`
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`
`644
`
`Lo et al.
`
`CLINICAL
`
`lWAP.MA COLOGY & THERAPEUTICS
`DECEMBER 1995
`
`HOUR
`
`Fig. 1. Mean plasma concentrations (in nanograms per milliliter) of losartan and EXP3174 in 12
`subjects after the administration of a single 20-minute intravenous infusion dose of 20 mg losartan
`(open circles,
`losartan; squares,
`EXP3174) and a single 50 mg oral dose of losartan (inverted
`tri-
`losartan; triangles,
`EXP3174) in study 1.
`angles,
`
`limits of quantification
`ultraviolet detection. l6 The
`for
`losartan or EXP3174 were 5 rig/ml
`in plasma
`and 10 rig/ml
`in urine. Quality control samples for
`losartan and EXP3174
`in plasma and urine (at con-
`centrations of 20, 80, and 800 rig/ml for plasma and
`40, 160, and 1600 rig/ml for urine) were included
`in
`each analytic
`run and the
`interday coefficients of
`variation
`throughout
`the study assay periods were
`<5%.
`
`ratio
`distribution
`concentration
`Blood-to-plasma
`The blood-to-plasma distribution
`ratios of losartan
`and EXP3174 were measured in fresh human blood
`from four donors. Losartan and EXP3174 were added
`to whole blood to give final concentrations of 20, 200,
`and 800 rig/ml (in triplicate at each concentration). Af-
`ter incubation at 37” C for 30 minutes, samples were
`centrifuged, and the concentrations of losartan and
`EXP3174
`in plasma were determined by HPLC. The
`
`ratio was
`to plasma concentration distribution
`blood
`calculated as the nominal concentrations
`in blood to
`the found concentrations in plasma.
`
`analyses
`Pbarmacokinetic
`curve
`The area under the plasma concentration-time
`(AUC) up to the last measured time point [AUC(O-t)]
`for both
`losartan and the metabolite EXP3174 were
`calculated with use of the linear trapezoidal method
`for ascending concentrations and the log-trapezoidal
`method
`for descending concentrations. Values
`for
`AUC(O-m) were obtained by summing AUC(O-t) and
`AUC(t-w),); the latter was obtained by dividing
`the last
`measured plasma concentration by the terminal dispo-
`sition rate constant (h) which was estimated by regres-
`sion of the terminal
`log-linear plasma concentration
`time points. Terminal disposition half-life
`(tl/,) was
`calculated as the quotient of the natural log of 2 and A.
`Harmonic mean half-lives and their pseudo standard
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`Fig. 2. Mean plasma concentrations of losartan and EXP3174 in six subjects after the administra-
`tion of a single 20-minute intravenous infusion of 30 mg losartan (circles,
`losartan; squat-es,
`EXP3174 formed from losartan), and a single 20-minute intravenous infusion dose of 20 mg
`EXP3174 (diamonds,
`EXP3174), study 2.
`
`deviations were calculated according to the method of
`Lam et a1.17 Volume of distribution at steady-state
`(V,,) after infusion was calculated according
`to the
`method of Perrier and Mayersohn.‘s Urinary recover-
`ies of losartan and EXP3174 were expressed as the
`percentage of dose administered, with EXP3174 being
`corrected for molecular weight (MW 461.015
`for lo-
`sartan potassium and 436.905
`for E-3174 free acid).
`Renal clearance of losartan and EXP3174 was calcu-
`lated as the quotient of the amount excreted in urine
`and the corresponding plasma AUC over the same
`time interval.
`The
`fraction of the
`converted systemically
`lated as follows’“:
`f,,=AUC ,xxm,7zt,D,v CL,x,,dQv
`MW,os/MW,m,,,,
`in which AUC,,,a
`r 74,Div is the area under the metabo-
`lite EXP3 174 plasma concentration-time
`curve after
`
`losartan
`intravenous dose of
`to EXP3174
`(fi,) was calcu-
`
`intravenous administration of the parent drug losartan,
`is the systemic clearance of EXP3174, D,,
`CLEXP3174
`is the intravenous dose of parent drug losartan, and
`MW,,, and MWExp3 l74 are the molecular weights of
`losartan and EXP3 174, respectively. Similarly,
`the
`overall fraction of an oral dose of losartan that is con-
`verted to EXP3 174 by both presystemic and systemic
`mechanisms (f,,) was estimated by the following ex-
`pression:
`
`is the area under the me-
`in which
`AU&m
`174,Dpo
`tabolite EXP3 174 plasma concentration-time curve af-
`ter oral administration of the parent drug losartan, and
`D,,
`is the oral dose of losartan. The contributions of
`presystemic and systemic conversion after oral losar-
`tan were estimated as follows. Because bioavailability
`(F) and systemic conversion (f,,) could be estimated,
`
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`
`646
`
`Lo et al.
`
`CLINICAL
`
`P HARMACOLOGY
`
`& THERAPEUTICS
`DECEMBER 1995
`
`Table II. Summary pharmacokinetics of losartan and EXP3174 after 100 mg losartan oral solution and a single
`20-minute
`intravenous infusion dose of 30 mg losartan in six healthy male subjects in study 2”
`Losartan
`V
`d
`
`ti/2
`(hr)
`
`CL
`(mllmin)
`
`CL,
`(mllmin)
`
`in
`
`%Dose
`urine
`
`Oral F
`(%I
`
`Subject
`No.
`
`C,,,
`(@ml)
`
`;z;
`
`AUC (ng
`
`hrlml)
`
`486
`358
`599
`798
`664
`1051
`659
`244
`
`losartan
`
`-
`
`Oral
`
`losartan
`1
`2
`3
`4
`5
`6
`Mean
`SD
`Intravenous
`1
`2
`3
`4
`5
`6
`
`Mean
`SD
`
`0.5
`0.3
`0.3
`0.3
`1.0
`0.5
`
`0.5
`0.3
`
`-
`
`-
`
`726
`565
`1045
`1209
`1619
`1384
`
`1091
`397
`
`679
`896
`502
`913
`932
`1185
`
`851
`235
`
`2.5
`2.5
`2.4
`3.0
`4.6
`3.0
`
`2.9t
`0.6t
`
`4.2
`3.2
`2.3
`2.9
`4.6
`3.0
`
`3.2t
`o.st
`
`-
`
`-
`
`-
`
`-
`-
`
`65.1
`26.4
`53.9
`32.4
`73.9
`27.8
`
`46.6
`20.5
`
`-
`
`-
`
`-
`
`661.5
`506.0
`886.5
`495.2
`437.3
`365.8
`
`558.7
`188.0
`
`75.5
`44.6
`87.2
`63.9
`72.1
`44.5
`
`64.6
`17.3
`
`71.5
`36.7
`101.0
`69.4
`75.9
`31.9
`
`64.4
`26.0
`
`3.7
`1.7
`6.3
`5.1
`7.7
`4.1
`
`4.8
`2.1
`
`10.8
`7.2
`11.6
`13.9
`16.8
`8.7
`
`11.5
`3.5
`
`32.2
`18.6
`61.9
`39.8
`47.0
`34.0
`
`38.9$
`14.7
`
`-
`
`*Mean actual doses were 90.3 and 26.4 mg losartan potassium after oral and intravenous
`tHarmonic mean and pseudo standard deviation.
`$Geometric mean is 36.5%.
`
`administrations,
`
`respectively.
`
`the contribution of systemic conversion after oral lo-
`sartan is therefore:
`
`fiv F
`
`and the presystemic contribution of EXP3174
`oral losartan is therefore:
`fpo - (fiv F)
`
`from
`
`RESULTS
`ratio
`distribution
`concentration
`Blood-to-plasma
`in
`Both losartan and EXP3174 distributed primarily
`the plasma component of human whole blood. The
`blood to plasma concentration distribution ratio values
`averaged 0.53 and 0.58 for losartan and EXP3174, re-
`spectively. The ratios were independent of concentra-
`tions from 20 to 800 rig/ml. The low ratio is not unex-
`pected because both compounds are highly bound to
`plasma proteins, mainly to albumin. The percentage of
`bound values in plasma were 98.7% and 99.8% for lo-
`sartan and EXP3 174, respectively.20
`
`Study 1
`The pharmacokinetics of losartan and EXP3174 af-
`ter oral and intravenous
`losartan are summarized
`in
`Table 1. Mean concentration-time
`profiles for losartan
`and EXP3174 are shown in Fig. 1. The mean plasma
`
`clearance of losartan was 636 ml/min (8.6 ml/min/kg)
`and V,, was 28.4 L (0.38 L/kg). Terminal half-life of
`losartan was 1.8 hour. After oral administration of the
`50 mg losartan
`tablet, plasma losartan peaked at 1
`hour and then declined polyexponentially, with a ter-
`minal tl/, of 2.1 hours. The bioavailability of losartan
`was 32.6% (geometric mean; range, 12.1% to 66.6%).
`The metabolite EXP3174 peaked at 4 hours and then
`declined polyexponentially, with a terminal
`tl/, of 6.4
`hours (range, 3.9 to 14 hours). The plasma AUC of
`EXP3174 was higher than that of losartan. After oral
`administration of losartan, the AUC values were 476
`and 1915 ng . hr/ml for losartan and EXP3174, respec-
`tively. The corresponding values after intravenous lo-
`sartan were 539 and 744 ng . hr/ml, respectively. On
`average, 4.2% and 6.1% of an oral losartan dose were
`excreted in the urine as losartan and EXP3 174, respec-
`tively. The renal clearances of losartan and EXP3174
`were 72 and 26 ml/min, respectively.
`
`Study 2
`The pharmacokinetics of losartan and EXP3174 af-
`ter oral and intravenous losartan and after intravenous
`EXP3174 are summarized in Tables II and III. Fig. 2
`shows the mean profiles for losartan and EXP3174 af-
`ter intravenous losartan, as well as for EXP3174 after
`
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`AUC
`hrlml)
`
`(ng
`
`3044
`3713
`4222
`5389
`2468
`5599
`
`4013
`1253
`
`780
`1322
`1540
`1632
`741
`1976
`
`1332
`490
`
`f /,+
`(hr)
`
`7.8
`9.2
`6.9
`7.2
`8.2
`8.3
`
`7.9t
`0.8.t
`
`5.7
`3.3
`5.5
`4.6
`6.1
`11.9
`5.3-I
`2.1:
`
`455
`737
`511
`872
`338
`1002
`
`653
`259
`
`64
`233
`151
`200
`42
`203
`149
`19
`
`2.0
`2.0
`3.0
`2.0
`3.0
`2.0
`
`2.3
`0.5
`
`4.0
`2.0
`3.0
`3.0
`X.0
`4.0
`4.0
`2.1
`
`EXP 3 I 74
`
`Y \
`CL)
`
`CL
`(mllmin)
`
`CL,<
`(mllmin)
`
`in
`
`7~Do.w
`urine
`
`31.5
`21.2
`35.8
`28.0
`25.7
`19.8
`
`27.0
`6.1
`
`35.1
`20.1
`29.3
`26.6
`25.4
`15.1
`25.3
`7.0
`
`6.8
`5.4
`10.6
`10.6
`4.5
`7.9
`
`7.6
`2.6
`
`6.5
`6.5
`10.4
`10.3
`4.7
`7.1
`
`7.6
`2.3
`
`-
`
`-
`
`-
`
`-
`
`-
`
`intravenous EXP3 174. The plasma clearance values
`of
`losartan and EXP3174 were 559 ml/min
`(7.2
`ml/min/kg) and 47 ml/min
`(0.60 ml/min/kg),
`respec-
`tively; V,, values were 47 L (0.58 L/kg) and 10 L
`(0.13 L/kg), respectively; and renal clearances were 64
`and 26 ml/min,
`respectively. The systemic conversion
`of losartan to EXP3174 was 14.3% (range, 8.2% to
`17.7%; Table IV). The fraction of an oral dose of lo-
`sat-tan that was converted
`to EXP3 174 was 13.6%
`(range, 7.4% to 17.0%). Presystemic conversion con-
`tributed 8.0% and systemic conversion contributed
`5.6%. The bioavailability of the oral losartan solution
`was similar
`to that of the tablet, 36.5% (geometric
`mean; range, 18.6% to 61.9%).
`The mean plasma clearance of losartan after intrave-
`nous losartan from the 18 subjects in the two studies was
`610 ml/min (8.1 ml/min/kg). Mean renal clearance was
`70 ml/min. Mean percentage of the intravenous dose ex-
`creted in urine as intact losartan was 12%. Mean V,, was
`34 L (0.45 L/kg). Mean terminal tl/, was 2.1 hours.
`
`DISCUSSION
`Losartan potassium is a new, orally active antihy-
`pertensive agent that acts by specifically blocking the
`of angiotensin
`IT at the AT,-subtype
`receptor.
`actions
`Results reported here characterize the disposition of
`
`losartan and its active metabolite EXP3174 in healthy
`male subjects and provide data of relevance to the
`clinical use of this agent.
`The mean plasma clearance of losartan is about 610
`ml/min, and
`the nonrenal clearance
`is about 540
`ml/min.
`In contrast, compared with
`losartan
`the
`plasma clearance of EXP3174
`is very low-47 ml/
`min. Although
`renal excretion of intact losartan is a
`minor elimination pathway for losartan (12% of clear-
`ance of losartan), renal excretion is a major pathway for
`EXP3174, accounting for 55% of its clearance. How-
`ever, despite the major
`role of renal excretion
`for
`EXP3 174, plasma concentrations of EXP3 174 were not
`significantly elevated in patients with severe renal im-
`pairment.‘l The volume of distribution of losartan and
`EXP3174 are both relatively low: 34 L for losartan and
`10 L for EXP3174. The mean terminal ti/z of losartan is
`short relative to EXP3174: 2.1 hours versus 6.3 hours.
`After oral administration of losartan, peak concentra-
`tions of losartan are reached in 1 hour. Peak concentra-
`tions of EXP3174 are reached in 3% hours. The plasma
`AUC of EXP3 174
`is about
`four
`times
`that of losartan.
`The systemic
`availability
`of oral
`losartan
`is about
`one-third
`that of
`intravenous
`losartan.
`The
`low
`bio-
`availability
`could
`be due
`to a combination
`of
`incom-
`plete absorption and first-pass metabolism. With use
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`648
`
`Lo et al.
`
`CLINICAL
`
`P HARMACOLOGY
`
`& THERAPEUTICS
`DECEMBER 1995
`
`Table III. Summary pharmacokinetics of EXP3174 after a single 20-minute
`EXP3174 in six healthy male subjects in study 2”
`Subject
`AK
`(ng
`hrlml)
`No.
`
`tv2 fhr)
`
`vs, fL)
`
`intravenous infusion of 20 mg
`
`CL,
`(mllmin)
`
`in
`
`%Dose
`urine
`
`CL
`(mllmin)
`
`1
`2
`3
`4
`5
`6
`Mean
`SD
`
`5262
`5488
`5253
`6405
`6707
`6701
`
`5969
`709
`
`4.5
`7.5
`6.7
`6.2
`6.4
`7.4
`
`6.37
`1.47
`
`9.8
`10.4
`12.2
`9.3
`9.4
`11.0
`
`10.3
`1.1
`
`51.9
`52.0
`52.6
`43.4
`40.2
`41.6
`
`46.9
`5.8
`
`28.5
`22.1
`35.4
`26.5
`22.8
`20.0
`
`25.9
`5.6
`
`55.3
`42.4
`67.4
`61.0
`56.5
`47.9
`
`55.1
`9.0
`
`*Dosing
`tHamonic
`
`salt, concentrations
`solution as hydrochloride
`mean and pseudo standard deviation.
`
`assayed by HPLC as free acid. Mean actual dose was 16.6 mg of EXP3174
`
`free acid.
`
`Table IV. Oral bioavailability of losartan and extent of conversion to the active metabolite EXP3174 after
`intravenous and oral administration of losartan to healthy male subjects in study 2
`
`Subject No.
`
`1
`2
`3
`4
`5
`6
`Mean
`SD
`
`10.7
`15.4
`17.0
`16.6
`8.2
`17.7
`14.3
`3.9
`
`*Geometric mean is 36.5%.
`
`Contribution
`presystemic
`
`from
`losartan
`
`f PO
`from
`Contribution
`systemic losartan
`
`Total
`
`Oral bioavailability
`
`8.4
`10.2
`5.1
`10.3
`3.6
`10.7
`
`8.0
`3.0
`
`3.4
`2.8
`10.7
`6.7
`3.9
`5.8
`
`5.6
`2.9
`
`11.8
`13.0
`15.8
`17.0
`7.4
`16.5
`
`13.6
`3.6
`
`32.2
`18.6
`61.9
`39.8
`47.0
`34.0
`
`38.9*
`14.7
`
`the
`ratio of 0.53,
`of a blood-to-plasma distribution
`nomenal blood clearance of losartan is about 1020
`ml/min.
`If complete absorption of losartan from
`the
`gastrointestinal
`tract is assumed and if the liver is as-
`sumed to be the sole eliminating organ, one can pre-
`dict the bioavailability
`resulting from first-pass hepatic
`metabolism. With use of a normal
`liver blood
`flow
`value of 1500 ml/min,”
`the estimated hepatic extrac-
`tion ratio of losartan is 0.68. The predicted bioavail-
`ability value is therefore 0.32, which agrees well with
`the observed oral bioavailability value of 0.36 (arith-
`metic mean).
`The extent of conversion of losartan to the active
`carboxylic acid EXP3174 in humans was similar after
`oral and intravenous administration, about 14%. Al-
`though only a modest fraction of a dose of losartan
`was converted
`to EXP3174,
`relatively high plasma
`concentrations of EXP3174 were observed when com-
`pared with losartan. That is because the clearance of
`EXP3174 is tenfold lower than that of losartan. From
`the oral conversion data, both presystemic (8%) and
`
`to
`systemic (6%) conversions contributed significantly
`the formation of this metabolite after oral administra-
`tion. The terminal slope of EXP3174 after intravenous
`losartan administration was similar
`to that observed
`when
`the metabolite was given
`intravenously. This
`suggests that the elimination of EXP3174
`in subjects
`given losartan is not rate-limited by its formation rate.
`In conclusion, the pharmacokinetics of losartan and
`its active metabolite EXP3174 have been character-
`ized in healthy male subjects after intravenous
`losar-
`tan, intravenous EXP3174 and oral losartan adminis-
`trations. Despite a low conversion of
`losartan
`to
`EXP3174,
`concentrations of EXP3174 are higher
`when compared with losartan because of a low clear-
`ance of EXP3174. Both presystemic and systemic
`mechanisms contributed
`to the conversion of losartan
`to EXP3174. Although
`losartan is mainly eliminated
`by nonrenal mechanism, EXP3174
`is eliminated by
`both renal and nonrenal routes. The low oral bioavail-
`ability of losartan is mainly attributable
`to first-pass
`metabolism. These results are generally relevant to the
`
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`
`administration of losartan to patients with hyperten-
`sion. The relatively high concentrations of EXP3 174
`and the longer tl12 of EXP3174 contribute to its impor-
`tant role in the duration of action of losartan.
`
`4.
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