BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 11, 507-518 (1990)

THE RELATIONSHIP BETWEEN THE PHARMACOKINETICS OF IBUPROFEN ENANTIOMERS AND THE DOSE OF RACEMIC IBUPROFEN IN HUMANS ALLAN M. EVANS*?, ROGER L. NATION*, LLOYD N . SANSOM* AND ANDREW A . SOMOGYI~S

,FELIX BOCHNER~S

*School of Pharmacy, South Australian Institute of Technology, Adelaide, 5000; ?Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, 5000 and $Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, 5000

ABSTRACT Ibuprofen is a chiral drug which is used clinically as a racemate. The pharmacological properties of ibuprofen reside almost exclusively with the S( +)-enantiomer. However, a portion of R( -)-ibuprofen is metabolically inverted to its pharmacologically active, mirror-image form. To investigate the influence of increasing dose of racemic ibuprofen on the pharmacokinetics of its individual enantiomers, four healthy male volunteers were given racemic ibuprofen (200, 400, 800, and 1200mg), orally, on four occasions. The study was conducted using a balanced cross-over design. The extent of absorption of ibuprofen, as assessed by the total urinary recovery of ibuprofen and its metabolites, was extensive and independent of the administered dose. At all four doses, the area under the total and unbound plasma concentration-time curves (AUC and AUC,, respectively), and the unbound fraction in plasma, were significantly greater for the S(+)enantiomer. With increasing ibuprofen dose, there was a less than proportional increase in the AUC of each enantiomer, while the AUC, for both enantiomers increased in direct proportion to the administered dose. The time-averaged unbound fraction of each enantiomer increased significantly with increasing dose, which caused the non-linearity between AUC and dose. It was predicted that the metabolic intrinsic clearance of each enantiomer, and the fraction of R( -)-ibuprofen which was metabolically inverted to S( +)-ibuprofen, was independent of the administered dose. KEY WORDS

Ibuprofen Enantiomers Pharmacokinetics Dose-ranging Enantioselectivity

INTRODUCTION The 2-phenylpropionic acid (2-PPA) derivative, ibuprofen, is a non-steroidal anti-inflammatory agent used extensively in the treatment of osteoarthritis, rheumatoid arthritis, and related conditions. Ibuprofen contains a chiral carbon atom on the propionic acid side-chain, and therefore exists as two enantiomers. Correspondenceto Dr Roger L. Nation, School of Pharmacy, South Australian Institute of Technology, North Terrace, Adelaide, Australia 5000.

0 142-2782/90/060507-12$06.00 0 1990 by John Wiley & Sons, Ltd.

Received 18 May 1989 Revised 20 November 1989

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A. M. EVANS ET AL.

The anti-inflammatory, analgesic and antipyretic activities of ibuprofen arise from the ability of its S(+)-enantiomer (S-I) to inhibit the synthesis of prostaglandins.' Because ibuprofen is used clinically in its racemic form, one might expect half of the administered dose to be devoid of therapeutic activity. However, it is well documented24 that one of the metabolic pathways of R(-)ibuprofen (R-I) is chiral inversion to its pharmacologically active mirror-image form (S-I). Lee et aL3 have estimated that after oral administration of R-I (400 mg) to four healthy subjects, an average of 63 per cent was inverted to S-I. Chiral inversion has been reported for a number of other 2-PPA derivatives, including benoxapr~fen,~,~ fen~profen,~ cicloprofen,* and 2-PPA i t ~ e l f . ~ Although the mechanism of the inversion is not fully understood, it appears to proceed via the formation of a coenzyme A thioester of the R( -)-enantiomer of the 2-PPA derivative.2J0 It is well recognized that the plasma concentrations of ibuprofen do not increase in direct proportion to the administered dose."J2 Lockwood et a l l 2 administered racemic ibuprofen (400 to 1200mg) to healthy volunteers and found a less than proportional increase in the area under the total (bound plus unbound) plasma ibuprofen concentration-time curve (AUC) with dose. However, the area under the plasma concentration-time curve with respect to unbound drug (AUC,) increased in direct proportion to dose. Because the extent of absorption of ibuprofen (as gauged by the total urinary recovery of ibuprofen and its metabolites) was independent of dose, the authors suggested that ibuprofen clearance based on unbound drug was constant over the dose range examined.I2However, the plasma concentrations of ibuprofen were measured non-enantioselectively and the results provide no information regarding the effect of increasing dose of racemic ibuprofen on the pharmacokinetics of its individual enantiomers. Hence, the aim of the present study was to examine the relationships between the magnitude of the dose of racemic ibuprofen and the total and unbound plasma concentration-time profiles of its individual enantiomers and, in so doing, elucidate the influence of ibuprofen dose on the metabolic inversion pathway. METHODS Subjects and study design

Four non-smoking male volunteers ranging in age from 23 to 28 years, and weighing between 65 and 78 kg, participated in the study. Each volunteer underwent a medical examination, which included haematological, biochemical, and urinary analyses, and was assessed to be healthy by the examining physician. Exclusion criteria included a recent history of drug ingestion, a history of gastrointestinal, renal, respiratory, hepatic or blood coagulation disorders, and a known allergy to ibuprofen or any other non-steroidal anti-inflammatory agent.

IBUPROFEN KINETICS

509

Volunteers were instructed to abstain from all other drugs during the study. The study protocol was approved by the Ethics Committees of the Royal Adelaide Hospital and the University of Adelaide and all volunteers gave written, informed consent to their participation. All volunteers completed the study and no adverse effects were reported. Using a four-way, balanced cross-over design, each volunteer received racemic ibuprofen (200,400, 800, and 1200mg), orally, on four separate occasions. Ibuprofen was administered as one 200 mg or one, two or three 400 mg Brufen@ tablets (Boots Co., UK). The content accuracy and uniformity of each tablet batch were confirmed in our laboratory prior to the study. Ibuprofen was administered with 200ml of water after an overnight fast of 12h duration. A snack was permitted 2 h after dosing and a standard meal was supplied a further 2 h later. Blood samples (10ml) were collected via a cannula inserted into an arm vein, prior to dosing and at the following times thereafter: 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5 , 6, 8, 10, and 12h. Additional blood samples were collected by venipuncture after 24 and 48 h. Immediately after collection, plasma was separated and retained at - 18" until assay. A pre-dose urine sample was collected, as was all urine voided by each volunteer during the following time intervals after dosing: 0-12 h, 12-24 h and 24-36 h. After measurement of urinary volume, an aliquot of each sample was retained at - 18" until assay. Drug analyses in biologicaljuids Plasma samples were analysed for total concentrations of R-I and S-I using an enantioselective assay which involved conversion of the ibuprofen enantiomers to diastereomeric amides prior to HPLC. l 3 The unbound fractions of R-I and S-I in plasma were measured using an enantioselective technique which involved the use of radiolabelled racemic ibuprofen, equilibrium dialysis, derivatization of ibuprofen enantiomers to diastereomeric amides, HPLC, and radiochemical analysis. l 4 The unbound concentration of each enantiomer in plasma was calculated as the product of its total (bound plus unbound) plasma concentration and its unbound fraction. After alkaline hydrolysis of glucuronide conjugates, the urinary concenacid trations of ibuprofen, 2-[4-(2-hydroxy-2-methylpropyl)phenyl]propionic (referred to subsequently as hydroxy-ibuprofen) and 2-[4-(2-~arboxypropyl)phenyllpropionic acid (referred to as carboxy-ibuprofen) were measured by HPLC, based on a method described by Lockwood and Wagner.15 Data analysis The plasma concentration-time profiles of total R-I and total S-I were analysed in an identical manner. The terminal slope, determined by log-linear regression of at least the final three data points, was used to calculate the

510

A.

M. EVANS ET A L .

terminal rate-constant and the terminal half-life (tl/,).The area under the curve from time zero to infinity (AUC) was determined by summing the area from time zero to the time of the last measured concentration, determined by the linear trapezoidal method, and the extrapolated area. The extrapolated area was determined by dividing the final plasma concentration (interpolated from the log-linear regression analysis) by the terminal rate-constant, and in all cases this area accounted for no more than 10 per cent of AUC. The AUC for unresolved ibuprofen (RS-I), which represents that which would be determined if ibuprofen was measured using a non-enantioselective assay, was calculated by summing the AUC values of R-I and S-I. The peak plasma concentration (Cmax)and the time of its occurrence (t,,,) for each enantiomer were obtained directly from the experimental observations. For each volunteer, the unbound concentrations of R-I and S-I were determined in six plasma samples from each dose. The six samples were selected on the basis that they provided accurate representations of the plasma concentration-time profiles for total R-I and total S-I. For each enantiomer, the area under the unbound plasma concentration-time curve (AUC,) was determined as described above except that, because of the more protracted spacing of data points, the post-C,,, areas were determined using the logarithmic trapezoidal method. In all cases, the extrapolated area accounted for no more than 10 per cent of AUC,. The AUC, of RS-I was obtained by summing the AUC, values of R-I and S-I. For each enantiomer, the quotient of AUC, and AUC was taken to represent the time-averaged unbound fraction All data are presented as arithmetic mean f standard deviation. Two-tailed Student’s paired t-tests were used to compare the pharmacokinetic parameters of R-I with those of S-I at each dose level. Analysis of variance (ANOVA) was used to test for significant changes with dose in the pharmacokinetic parameters of R-I and s-I. In the cases of AUC and AUC,, ANOVA was performed after dose-normalization of the data. In addition, the 95 per cent confidence limits of the slope of the line relating AUC/dose, and AUC,/dose, to the administered dose was determined by linear regression. For both ANOVA and the Student’s t-test, p < 0.05 was chosen to represent statistical significance.

6).

RESULTS The plasma concentration-time profiles of total R-I, after the administration of 200, 400, 800, and 1200mg of racemic ibuprofen, in a single volunteer, are presented in Figure l(A). For clarity, the corresponding profiles for total S-I are presented in Figure l(B). AUC and AUC, of R-I The mean (fstandard deviation) t,,,, C,,,, t,, and S-I, over the range of doses examined, are presented in Table 1. As the dose of ibuprofen increased, there was a less than proportional increase in , of both enantiomers (Table 1). Although the non-linearity in the mean ,,C

fu,

1

-

I

I

' . . ' . ' 4.0 6.0 8.0 10.0 12.0

E

Hours

.1 0.0

1 2.0

4.0

Hours

6.0

B. Total S-l

8.0 10.0 12.0

Figure 1. Plasma concentration-time profiles of (A) R-I and (B)S-I in a representative volunteer following oral administration of racemic ibuprofen (0200 mg, W 400 mg, 0 800 mg, and A 1200mg)

.l! . ' 0.0 2.0

a

([I -

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1:

1 ([I

10;

100 7

10

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A. Total R-l

512

A. M. EVANS ET A L .

Table 1. Mean (standard deviation) pharmacokinetic parameters of R( -)-ibuprofen and S( +)-ibuprofen following oral administration of four doses of racemic ibuprofen

200

S( +)-Ibuprofen R( -)-Ibuprofen Dose of RS-ibuprofen (mg) 400 800 1200 200 400 800

1200

1.13 (0.59)

1.38 (083)

1.57 1.81 (0.82) (0.85)

1.13 (0.59)

1.87 (1.29)

1.89 (0.74)

2.19 (0.62)

(mg 1-9

10.0 (3.3)

14.1 (6.6)

24.4 (9.6)

11.3 (1.7)

16.9* (6.8)

31.6* (8.4)

47.7* (1.8)

t YI (h)

1-86 (0.54)

3-23 (1.95)

2.13 4.24 (0.37) (2.19)

1.93 (0.36)

3.36 (2.43)

1.95 (0.41)

2.01 (0.26)

5

0.296 0.325 0.367 0.461 (0.013) (0.040) (0.059) (0.024)

tmax

(h) Cmax

( x 100)

29.5 (3.4)

0.484* 0.554* 0.596* 0.668* (0.025) (0.049) (0.047) (0.047)

AUC (mg min I-')

1433 (423)

2510 (462)

4414 (960)

5165 (796)

2620* (586)

4524* (699)

8485* (899)

12930* (1384)

AUC, (mgminl-')

4.21 (1.2)

8-09 (1.3)

16.2 (4.2)

23.9 (4.6)

12.6* (2.3)

24.8* (2.1)

50.6* (7.2)

85.9* (4.4)

*Statistically different @ < 0.05) from the corresponding value for R( -)-ibuprofen at the same dose level.

C,,, for R-I was evident over the complete range of doses, the C,,, for S-I increased proportionally between 400 and 1200 mg. ANOVA was used to test Although no significant change for changes with dose in t,,,, t , and (p > 0.05) was detected in the t,, or tlh of either enantiomer, the increase with dose infuof R-I and S-I (Table 1) was highly significant (p < 0.002). Linearity between AUC and dose was assessed by analysing the dose-normalized AUC data, presented graphically in Figure 2(A). For R-I there was a progressive decrease in AUC/dose as the dose of ibuprofen increased, while for S-I, the mean AUC/dose decreased between doses of 200 and 400mg, but remained virtually constant thereafter. The dose-normalized AUC of RS-I, also presented in Figure 2(A), demonstrated a progressive decrease as dose increased. The change in AUC/dose was significant (p < 0.05) for R-I, but failed to reach significance for S-I (p = 0.15) and RS-I (p = 0.079). When the dose-normalized AUC data for R-I, S-I, and RS-I were regressed against the administered dose, the slope of the linear regression line in all three cases was less than zero. For R-I and RS-I, the 95 per cent confidence interval of the slope excluded zero. Hence, both statistical tests indicate a significant nonlinear relationship between dose and AUC for R-I. The relationship between dose-normalized AUC, and ibuprofen dose is shown for R-I, S-I, and RS-I in Figure 2(B). For each enantiomer, and for RS-I, ANOVA indicated no difference in AUC,/dose across the four doses. In all three cases, the 95 per cent confidence interval of the slope of the regression line relating AUCJdose, to the dose administered, included zero.

5.

513

IBUPROFEN KINETICS

r 0 0

cu

T

0 0

03

0 0

*

0

0

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0

0 03

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0 0 03

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0 0 (v

514

A. M. EVANS E T A L .

Table 2. Urinary recoveries of ibuprofen and its metabolites following alkaline hydrolysis of glucuronide conjugates. Data are expressed as the mean (standard deviation) recoveries as a percentage of the administered dose* ~

200 mg

Dose of RS-ibuprofen 400 mg 800 mg

~~~~

1200 mg

Ibuprofen Hydroxy-ibuprofen Carboxy-ibuprofen Total recovery

25-3 (1.7) 43.8 (7.7)

24.4 (2.9) 44.2 (6.3)

25.7 (3.3) 49.2 (8.4)

243 (3.7) 46.3 (11.4)

8 1.2 (7.2)

79.4 (8.0)

86.5 (10.1)

82.2 (13.1)

*Analysis of variance indicated that there was no significant difference in the urinary recovery of each species, and in the total recovery, over the four dosages.

There was no significantchange with dose in the urinary recovery of ibuprofen and its major metabolites, and the total sum of these recoveries (Table 2).

DISCUSSION The absorption of both ibuprofen enantiomers was, in general, rapid, and in all 16 treatments the peak concentrations of R-I and S-I were achieved within 3 h of dosing. The t,, of R-I and S-I were not significantly different, and did not change significantly with increasing ibuprofen dose. With one exception, C,, of S-I exceeded that of R-I, and the magnitude of the difference between the mean C,, of R-I and that of S-I increased with dose from 13 per cent at 200 mg through to 62 per cent at 1200mg (Table 1). At all four doses, there was no difference between the enantiomers in the mean tlh (Table 1). In a number of cases (see for example Figure 1A) the terminal portion of the plasma total concentration-time profile for R-I displayed a biphasic pattern, and this added considerable variability to the t H data for this enantiomer. For one volunteer, after the 400mg dose, the t X of R-I and S-I (6.04 and 6.99 h, respectively) greatly exceeded the corresponding estimates determined in the same volunteer at the other three dose levels. This was most likely due to a protracted absorption phase, resulting in a ‘flip-flop’ plasma concentration-time profile for the individual enantiomers, whereby the terminal slope represents drug absorption rather than elimination. Interestingly, there was no apparent reduction in the extent of absorption of ibuprofen in this case, since 77.7 per cent of the administered dose was recovered in the urine. The ratio of the AUC, of S-I to that of R-I in this case was 3.78, which

IBUPROFEN KINETICS

515

was not different from the corresponding ratio in the same individual at the other three doses (3.49 f 0-66). At all four dose levels, there was a statistically significant difference (p c 0.01) between thefuof R-I and S-I (Table l), and, for both enantiomers,fuincreased significantly with dose. These findings are consistent with a recent report from our laboratory that the plasma protein binding of ibuprofen exhibits concentration-dependence and enantioselectivity.l 4 For all 16 treatments, AUC and AUC, for S-I were substantially greater than for R-I, and the differences were significant at all four dose levels (p < 0.05). The mean AUC values of R-I and S-I after the 800 mg dose (Table 1) compare favourably with the values reported by Lee et ~ 1 after . ~ the oral administration of the same dose of racemic ibuprofen. In addition, the range of values for the AUC of RS-I found in the present study between the 400 mg and the 1200 mg doses (determined by summing the corresponding AUC values for R-I and S-I), are similar in magnitude to those values reported by Lockwood et a1.'2 The influence of dose on the pharmacokinetics of R-I and S-I was examined using the compartment-independent physiological approach described by Wilkinson and Shand.16For a drug which is cleared predominantly by hepatic biotransformation, such as ibuprofen,12J7the areas under the plasma concentration-time curve for total (AUC) and unbound (AUC,) species, after a single oral dose, are given by the following equations:

FG.D AUC, = Clint where FG is the fraction of the administered dose ( D ) which is absorbed from the gut into the hepatic portal vein, fu is the fraction unbound in plasma and Clint, the intrinsic clearance of the drug, is a measure of the ability of the liver to clear the drug in the absence of any organ flow or blood-binding restrictions. A large fraction of an orally administered dose of ibuprofen is recovered, as unchanged drug plus metabolites, in the urine (Table 2).12J3J7For this reason, the total percentage recovery of an orally administered dose of ibuprofen serves as a useful and convenient index of the extent to which it was absorbed from the gastrointestinal tract. The urinary recovery data from the present study (Table 2) suggest that the extent of ibuprofen absorption was dose-independent. The high percentage recovery also indicates that any difference in the extent of absorption between R-I and S-I was minor. Consequently, in the following discussion, it is assumed that for both R-I and S-I, FG is equal to unity. Therefore, for R-I, equations (1) and (2) become equations (3) and (4), respectively.

516

A. M.

EVANS E T A L .

The intrinsic metabolic clearance of R-I (C1;;I) is equal to the sum of the individual intrinsic clearances of the inversion and other metabolic pathways (oxidation and glucuronidation), and can be expressed as equation (5). Cli.;I = Cl.R-1,inv + Cl.R-l,other (5) int int The fraction of the administered dose of R-I which undergoes metabolic inversion (FZ)is therefore given by Cl,R-I,inv int Fr = Cl.R;I,inv + Cl.R-I,other int For S-I, after the administration of racemic ibuprofen (where DR-'equals DS-I), equations (1) and (2) can be written as equations (7) and (8), respectively.

It is instructive to consider the situation which would arise if Cli: and C1;;l,other were of equal magnitude. Under such conditions, AUC, of unresolved ibuprofen would be unaffected by changes in Cl:;l-inv. For example, a reduction in Cl$;l,invwould lead to a reduction in FI, and consequently AUC:-'. However, the reduction in AUC,S-*would be offset by an increase, of equal magnitude, in AUC,R-'. Hence, the sum of AUC,R-' and AUCt-' (i.e. AUC,RS-')would remain unchanged. and Clz: are, in From the data in Table 1 it can be shown that Clg;I>Other fact, of similar magnitude. Using the mean AUC, of R-I after the 800mg can be calculated to dose of the racemate (Table 1) and equation (4), CJlntR-I be 24.7 lmin-'. Lee et aL3 estimated that following a 400mg oral dose of R-I to four healthy adults, an average of 63 per cent was converted to S-I. This value was based upon measurement of AUC of S-I after administration of 400mg R-I and, on another occasion, 400mg S-I. As compared with the S-I phase, after administration of R-I the AUC of S-I was substantially lower and R-I was present concurrently in the plasma sample^.^ Therefore any concentration-dependent plasma binding of S-I, as was found in the present (vide supra) and previousk4studies, and/or interaction between R-I and S-I for plasma binding sitesI4may have introduced some error into the estimate of FI based on total plasma concentration reported by Lee and coworkers. If it is assumed that in the present study, after the 800 mg dose of racemic ibuprofen, an average

IBUPROFEN KINETICS

517

of 60 per cent of R-I was metabolized to S-I, CIE;l*invand C1$;l,othercan be estimated (equation (5)) to be 14.8 lmin-I and 9.9 lmin-I, respectively, and Cl:? (equation (8)) to be 12.6 lmin-l. Hence, if the previous assumptions are correct, CIK;l,otherand Cl:? are of similar magnitude. Therefore, as shown above, AUC, of unresolved ibuprofen may be relatively insensitive to changes in Cl;;l,inv, even though this latter parameter is an important determinant of the amount of the administered dose of racemic ibuprofen which is presented to the body as the active enantiomer. This illustrates the limited value of conducting pharmacokinetic studies on ibuprofen without measuring the total and unbound plasma concentrations of the individual enantiomers. The results of the present study suggest that the non-linear relationship, found by previous workers,"J2 between the administered dose of ibuprofen and AUC of unresolved drug, results mainly from non-linearity between dose and AUC for R-I. For this enantiomer, there was a relative decrease in AUC of 40 per cent over the dose range 200 to 1200mg. Because the extent of absorption of ibuprofen was dose-independent, this suggests that as the dose of racemic ibuprofen was increased, there was an increase in fuR-' and/or C&I (equation (3)). However, there was a linear relationship between AUC, of R-I and dose, which suggests that Cl;;I remained constant (equation (4)), and that the concentration-dependent plasma protein binding (Table 1) was the reason for the non-linearity between dose and AUC. For S-I, the non-linear relationship between AUC and dose was less apparent than for R-I, and failed to reach statistical significance. Enzyme kinetics predict that intrinsic clearance either remains unchanged or decreases in the presence of increasing concentrations of substrate. The constancy of C1K;I with increasing dose suggests that the individual intrinsic clearances of the major metabolic pathways of R-I also remained unchanged (equation ( 5 ) ) and, therefore, that FI was independent of dose (equation (6)). Hence, it would appear that the enzymatic processes involved in the inversion of R-I2 were not saturated within the range of R-I concentrations achieved. Given that ClEiI, and therefore FI, remained constant, the lack of dependence of AUC, of S-I on dose suggests (equation (8)) that Clintof S-I also remained unchanged throughout the dose range examined. In conclusion, the results indicate that in healthy volunteers, the disposition of ibuprofen was enantioselective over the therapeutic dose range. Both enantiomers exhibited concentration-dependent plasma protein binding which, for R-I, resulted in a non-linear relationship between AUC and dose. The fraction of administered R-I which was inverted to its mirror-image form was doseindependent. Importantly, over the range of doses used clinically, there were no dramatic changes in the dose-normalized AUC and AUC, of the active enantiomer, S-I. Although non-enantioselective studies have found ibuprofen pharmacokinetics to remain essentially constant upon chronic administration'8 and to vary little with age and disease ~ t a t e , ' further ~ . ~ ~ studies are required to elucidate whether the inversion process is altered under these conditions.

518

A. M. EVANS ET A L .

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The relationship between the pharmacokinetics of ibuprofen enantiomers and the dose of racemic ibuprofen in humans.

Ibuprofen is a chiral drug which is used clinically as a racemate. The pharmacological properties of ibuprofen reside almost exclusively with the S(+)...
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