IBUPROFEN DISPOSITION IN OBESE INDIVIDUALS

Transcription

1 1117 BUPROFEN DSPOSTON N OBESE NDVDUALS DARRELL R. ABERNETHY nd DAVD J. GREENBLATT Eleven obese subjects (weight 114? 11 kg, men f SE) nd 11 ge-mtched subjects with norml body weight (61 f 3 kg) were given 6 mg of ibuprofen orlly fter n overnight fst. Pek ibuprofen concentrtion ws significntly decresed in obese subjects (P <.2), lthough the time from dministrtion to pek concentrtion ws not different. buprofen volume of distribution ws incresed in obese subjects, nd this incresed distribution correlted positively with body weight (r =.82; P <.1). Volume of distribution corrected for body weight ws decresed in obese subjects, nd this decrese correlted negtively with body weight. buprofen clernce ws lso incresed in obese subjects; the increse correlted positively with body weight (r =.81; P <.1). Since the independent vribles, volume of distribution nd clernce, were incresed in prllel in the obese subjects, the dependent vrible, elimintion hlf-life, ws unchnged. Using men vlues of distribution clculted from the 2 groups, ibuprofen distribution into body weight in excess of idel body weight ws found to be pproximtely.44 times s extensive s the distribution into idel body weight. Furthermore, ibuprofen clernce incresed in prllel with the volume of distribution nd totl body weight. Cliniclly, these dt indicte tht in obese ptients, the ibuprofen dose my be incresed without chnging the dose intervl, in order to chieve necessry plsm concentrtions.. From the Deprtment of Medicine, Bylor College of Medicine, Houston, Texs nd the Division of Clinicl Phrmcology, Tufts-New Englnd Medicl Center, Boston, Msschusetts. Supported in prt by USPHS grnts AM nd MH nd by Reserch Fellowship from the Chrles A. King Trust of Bo,ston, Msschusetts. Drrell R. Abernethy, MD, PhD; Dvid J. Greenbltt, MD. Address reprint requests to Drrell R. Abernethy, MD, PhD, Deprtment of Medicine, Bylor College of Medicine, 826E, Houston, TX 773. Submitted for publiction Jnury 22, 1985; ccepted April 1, buprofen is nonsteroidl ntiinflmmtory gent tht is widely used in the mngement of pin nd rthritic disese (1,2). n obese individuls, the prevlence of disese processes for which ibuprofen is cliniclly indicted is very high. Such obese individuls my hve importnt ltertions in the distribution (3-5) nd clernce (6,7) of drugs, even in the bsence of other disese processes. buprofen disposition hs been evluted in helthy volunteers (8), elderly individuls (9,1), ptients with heptic dysfunction ( ), nd during concurrent dministrtion of other drugs (12-14); however, no dt re vilble regrding the disposition or dose recommendtions for obese ptients. We report here the effect of obesity on the disposition of single doses of ibuprofen. SUBJECTS AND METHODS Subjects. Eleven obese volunteers nd 11 volunteers with norml body weight prticipted in this study fter giving written informed consent. Subjects were in good helth, s documented by medicl history, physicl exmintion, nd lbortory exmintion, which included complete blood count, mesurement of electrolyte levels, liver nd kidney function tests, nd urinlysis. None of the subjects were tking ny mediction t the time of study, nor were ny of them on specil diet to induce weight loss. Three obese nd 4 control subjects were cigrette smokers. Obesity ws defined by devition from idel body weight (BW) s determined from cturil tbles (S): BW (mles): 11 bs 2 5 b/inch of height bove or below 5 ft; BW (femles): 1 bs 5 5 b/inch of height bove or below 5 ft. Percent BW ws determined by the following reltionship: Totl body weight?4 1BW = x 1 BW Arthritis nd Rheumtism, Vol. 28, No. 1 (October 1985)

2 1118 ABERNETHY AND GREENBLATT HOURS AFTER DOSE Figure 1. Plsm concentrtions of ibuprofen in representtive obese subject nd subject with norml body weight, fter receiving single orl dose (6 mg). This nthropometric index ws cross-vlidted with nother commonly used pproch, the body mss index (16), which is determined by: Weight (in kg) Height (in meters squred) Tble 1. Chrcteristics of study popultion nd phrmcokinetic vribles for ibuprofen* Chrcteristic Age Weight (kg) % BW BM Sex, M/F (n) Cigrette smokers, yes/no (n) Phrmcokinetic vrible Pek plsm concentrtion (wdml) Time to pek (hours) Elimintion hlf-life (hours) Volume of distribution (liters) Volume of distribution (litedkg) Clernce (mliminute) Free frction (% not bound to plsm protein) Obese Control subjects subjects (n = 11) (n = 11) 35 t t t ? 3.3 6/ t ? t ? t.3 36 t 4 61 t t t.51 6/ t 3.lf 1.25 t t t.7t.176 t.8t 59.2? 4.lt 1.4 t.4 * Vlues re men t SE. BW = idel body weight; BM = body mss index. See Subjects nd Methods for detils of clcultions. t P <.5 by Student's independent f-test. f P <.2 by Student's independent t-test. Obesity ws defined s weight >12% of BW, nd norml body weight ws defined s <115% of BW. Experimentl procedure. After n overnight fst, subjects took single 6-mg tblet of ibuprofen (Motrin; Upjohn, Klmoo, M), orlly, with 1-2 ml of wter. Subjects continued to fst for 3 hours fter drug dministrtion. Venous blood smples were drwn from n indwelling butterfly cnnul, which ws kept ptent by slow infusion (1 ml/hour) of physiologic sline for the first 8-1 hours fter the drug ws tken. Subsequent blood smples were obtined by seprte venipuncture into heprinied Vcutiner tubes. Blood smples were obtined before drug dministrtion nd t.25,.5,.75, 1, 3, 2, 2.5, 3,4,6, 8, 1, 12, 15, 18, nd 24 hours fter dministrtion. Blood smples were centrifuged, nd the plsm ws seprted nd froen t -2 C until the time of drug nlysis. Anlysis of plsm smples. buprofen plsm concentrtions were determined by high pressure liquid chromtogrphy using ultrviolet detection (17). The extent of ibuprofen binding to plsm protein ws determined by spiking duplicte plsm smples ( ml) with 4C-ibuprofen (5 nci) nd subjecting ech smple to equilibrium dilysis for 6 hours (18). Ech smple ws then nlyed in duplicte. Recovery of ibuprofen from the dilysis system ws complete, nd ibuprofen binding ws found to be concentrtion-independent over the low rnge of plsm concentrtions chieved in subjects in this study (8). Phrmcokinetic prmeters for ibuprofen fter dministrtion of the single dose were determined with the ssumption of complete systemic vilbility fter ingestion 3. - r c 2. - w 1.5 u Y 5 n 1. - W - O.! l m l o "T E -\ c U c % 3 u 2 2 -& Y w D 1. : 1 Figure 2. Left, Time from dministrtion of single orl dose of ibuprofen (6 mg) to ttinment of pek plsm ibuprofen concentrtion. Right, Pek plsm concentrtions chieved. = mles; = femles: brs show mens t SE.

3 BUPROFEN N OBESTY 1119 'i 3ot 2ok i Figure 3. Elimintion hlf-life (left), orl volume of distribution (center), nd orl clernce (right) of ibuprofen in obese nd control mle () nd fernle () subjects fter receiving single orl dose (6 mg). L ( 13,19). Apprent elimintion hlf-life ws clculted from the slope of the terminl log-liner phse (bet) of the plsm concentrtion-time curve. Are under the plsm concentrtion-time curve (AUC) ws determined by the trpeoidl method, from the time of drug dministrtion to the finl detectble plsm concentrtion, nd the residul AUC extrpolted to infinity ws determined by dividing the finl plsm concentrtion by bet. Apprent orl clernce nd volume of distribution of ibuprofen, ssuming 1% systemic vilbility fter orl dministrtion, were determined by dividing the dose by the AUC nd the clernce by bet, respectively (2). Differences between obese subjects nd control subjects were ssessed using Student's independent t-test. RESULTS n ll subjects, fter pek ibuprofen plsm conce:ntrtions were reched, disppernce of ibuprofein from plsm exhibited monoexponentil or biexponentil decline (Figure 1). The time between dministrtion of ibuprofen nd ttinment of pek ibuprofen concentrtion W ~ S no different between the 2 groups; however, pek plsm concentrtion chieved fter the sme 6-mg orl dose ws less in the obese subjects (Tble 1 nd Figure 2). Orl volume of distribution ws mrkedly incresed in obese subjects; however, when corrected for body weight, it ws less in the obese subjects compred with controls. This indictes tht ibuprofen distribution into body weight in excess of idel body weight is less extensive thn its distribution into idel body weight. When men vlues were used, distribu- *O r 16t "7 12 8t,o, Mles o Femles r =.82 p<o.ool r r =.81 p<o.ool 4 L Otl ~ ~ ~ TOTAL BODY WEGHT (KG) Figure 4. Reltion of totl body weight to ibuprofen orl volume of distributton (top) nd to ibuprofen orl clernce (bottom) in mle () nd femle () subjects fter single orl dose (6 mg).

4 112 ABERNETHY AND GREENBLATT tion into excess body weight ws.44 times s extensive s distribution into idel body weight (Tble 1 nd Figure 3). ncresed distribution in obese subjects ws highly correlted with incresed totl body weight (r =.82; P <.1) (Figure 4). Totl ibuprofen clernce ws lso incresed in obese subjects (Tble nd Figure 3) nd ws positively correlted with totl body weight (r =.81; P <.1) (Figure 4). Furthermore, totl volume of distribution nd totl clernce incresed in prllel cross these subject groups nd were well correlted (r =.79; P <.1). With the prllel increse in the independent vribles, volume of distribution nd clernce, the derived dependent vrible, elimintion hlf-life, ws no different between subject groups (Tble 1 nd Figure 3). The observed increses in volume of distribution nd clernce were not the result of chnges in ibuprofen plsm protein binding, since no difference ws noted between subject groups (Tble 1). DSCUSSON buprofen is biotrnsformed to hydroxyl nd crboxyl metbolites in 1 :2 rtio, nd is highly protein-bound (>99%) cidic drug which is restrictively clered ( low clernce drug); however, it hs short elimintion hlf-life becuse of its very limited distribution (8-13,21). These phrmcokinetic prmeters of elimintion re linked by the following reltionship:.693 X Vd tl/ = Clernce where the volume of distribution (V,) nd clernce re the independently mesured prmeters, nd elimintion hlf-life (t %) is the derived dependent vrible. Prior studies indicte tht orlly dministered ibuprofen is rpidly nd completely bsorbed (13,19). Assuming complete systemic vilbility in this study popultion, ibuprofen disposition in obese subjects demonstrted mrked difference from tht in subjects with norml body weight. The bsorption prmeter, time to pek concentrtion, ws no different between subject groups, indicting tht there ws no difference in the rte of bsorption. However, decresed pek plsm concentrtions chieved in the obese subjects (Figures 1 nd 2 nd Tble 1) probbly reflect more extensive distribution. The other potentil explntion for this finding, tht bsorption ws less complete in obese subjects, could not be evluted in this study becuse of the lck of n intrvenous ibuprofen formultion. However, it seems unlikely since obesity in the bsence of other disese processes or gstrointestinl surgicl procedures hs not been reported to ffect the extent of drug bsorption (22,23). The incresed volume of distribution of ibuprofen in obese subjects is similr to tht reported for other reltively hydrophilic drugs thsit hve limited distribution volume (3,4,6,24,25). For such drugs, this increse my represent distribution into the incresed totl body wter nd len body mss tht is present in obese humns (26). Unlike other low-clernce drugs tht undergo oxidtive biotrnsformtion, such s ntipyrine, diepm, desmethyldiepm, lprolm, nd cffeine (3,4,25,27), which hve miniml chnge in clernce in obese subjects, the orl clernce of ibuprofen incresed in prllel with incresed body weight nd with incresed distribution volume. buprofen undergoes liphtic hydroxyltion nd crboxyltion (21,28), unlike the ring hydroxyltion or oxidtive N-demethyltion biotrnsformtion pthwys of other drugs studied. t is possible tht this enymtic ctivity is incresed in obese individuls, since there is now considerble evidence tht subspecies of heptic cytochrome P-45 my be selectively induced or inhibited with no chnge in the ctivity of other subspecies (29). Furthermore, the specific enyme systems tht medite ibuprpfen biotrnsformtion re not well identified; however, they re resistnt to inhibition by cimetidine, which, for ll substrtes studied to dte, hs uniformly inhibited cytochrome P-45-medited drug biotrrisformtions in vivo in humns (14). buprofen is extensively bound to lbumin nd my exhibit nonlinerity in protein binding t high concentrtions (3). Binding ws essentilly concentrtion-independent, nd no difference between obese nd control subjects ws observed for the ibuprofen plsm concentrtions chieved during this singledose study. This is consistent with previous findings for the lbumin-bound drugs tht hve been evluted in obese subjects (3,4,7,27). Cliniclly, these dt indicte tht to ttin similr ibuprofen plsm concentrtions in obese ptients, the sie of ech dose should be incresed in morbidly obese subjects, with no chnge in the dose intervl. f n pproprite dose of 8 mg/kg (pproximtely 6 mg) is ssumed for ptient with norml body weight, the pproprite increment is: Dose = 6 mg + (totl body weight [in kg] - 7 kgl(3.5 rng/kg), or: (8 mg/kg - first 7 kg) + (3.5 rng/kg - weight in excess of 7 kg)

5 BUPROFEN N OBESTY 1121 such tht n individul weighing twice his or her BW (14 kg) my require dose of 6 mg + (7 kg)(3.5 mg/kg), or 845 mg, to ttin similr plsm ibuprofen concentrtion-time profile. ACKNOWLEDGMENTS We re grteful to Jerold S. Hrmt for ssistnce in sttisticl nlysis, Rit Mth for nlyticl ssistnce, Dr. Richrd. Shder for dvice nd support, nd the stff of the Clinicl Study Unit, New Englnd Medicl Center Hospitl. REFERENCES 1. Adms SS, McCullough KF, Nicholson S: The phrmcologicl properties of ibuprofen, n nti-inflmmtory gent, nlgesic, nd ntipyretic gent. Arch nt Phrmcodyn Ther 178: , Kntor TG: buprofen. Ann ntern Med 91: , Abernethy DR, Greenbltt DJ, Divoll M, Hrmt JS, Sbder R: Altertions in drug disposition nd clernce due to obesity. J Phrmcol ExpTher 217: , Abernethy DR, Greenbltt DJ: Phrmcokinetics of drugs in obesity. Clin Phrmcokinet 7: , Albernethy DR, Greenbltt DJ: Lidocine disposition in obesity. Am J Crdiol 53: , Abernethy DR, Divoll M, Greenbltt DJ, Ameer B: Effect of obesity nd sex on cetminophen disposition. Clin Phrmcol Ther 31:783-79, Abernethy DR, Greenbltt DJ, Divoll M, Shder R: Enhnced glucuronide conjugtion of drugs in obesity: studies of lorepm, oxepm, nd cetminophen. J Lb Clin Med , Lockwood GF, Albert KS, Gillespie WR, Bole GG, Hrkcom TM, Spunr GS, Wgner JG: Phrmcokinetic!j of ibuprofen in mn.. Free nd totl re-dose reltionships. Clin Phrmcol Ther 34: Albert KS, Gillespie WR, Wgner JG, Pu A, Lockwood GF: Effects of ge on the clinicl phrmcokinetics of ibuprofen. Am J Med 77:47-5, Greenbltt DJ, Abernethy DR, Mtlis R, Hrmt JS, Shder R: Absorption nd disposition of ibuprofen in the elderly. Arthritis Rheum 27: , Juhl RP, vn Thiel DH, Dittert LW, Albert KS, Smith RB: buprofen nd sulindc kinetics in lcoholic liver disese. Clin Phrmcol Ther 34: 14-19, Wright CE, Antl EJ, Gillespie WR, Albert KS: buprofen nd cetminophen kinetics when tken concurrently. Clin Phrmcol Ther 34:77-71, Albert KS, Gernt CM: Phrmcokinetics of ibuprofen. Am J Med 77:4-46, Conrd KA, Myersohn M, Bliss M: Cimetidine does not lter ibuprofen kinetics fter single dose. Br J Clin Phrmcol 18: , Weights of insured persons in the United Sttes ssocited with lowest mortlity. Sttisticl Bulletin of the Metropolitn Life nsurnce Compny, No. 4. New York, November-December, Frisncho AR, Flegel PN: Reltive merits of old nd new indices f body mss with reference to skinfold thickness. Am J Clin Nutr 36: , Greenbltt DJ, Arendt RM, Locniskr A: buprofen phrmcokinetics: use of liquid chromtogrphy with rdil compression seprtion. Arneimittelforsch 33: , Mrtyn JAJ, Abernethy DR, Greenbltt DJ: Plsm proiein binding of drugs fter severe burn injury. Clin Phrmcol Ther , Verbeeck RK, Blckburn JL, Loewen GR: Clinicl phrmcokinetics of nonsteroidl nti-inflmmtory drugs. Clin Phrmcokinet 8: , ). Gibldi M, Perrier D: Phrmcokinetics. New York, Mrcel Dekker, Lockwood GF, Wgner JG: High performnce liquid chromtogrphic determintion of ibuprofen nd its mjor metbolites in biologicl fluids. J Chromtogr 232: , Grrett ER, Suverkrup RS, Eberst K, Yost RL, L.et-y JP: Surgiclly ffected sulfisoxole phrmcokinetics in the morbidly obese. Biophrm Dryg Dispos 2: , Andresen PB, Dn P, Kirk H, Greisen G: Drug bsorption nd heptic drug metbolism in ptients with different types of intestinl shunt opertion for obesity: study with phegone. Scnd J Gstroenterol , Abernethy DR, Greenbltt DJ, Mtlis R, Gugler R: Cimetidine disposition in obesity. Am J Gstroenterol 79~91-94, Abernethy DR, Todd EL: Cffeine disposition in obese mn (bstrct). J Clin Phrmcol 24:49, Forbes GB, Welle SL: Len body mss in obesity. nt J Obes 7:99-17, Abernethy DR, Greenbltt DJ, Divoll M, Smith RB, Shder R: The influence of obesity on the phrmcokinetics of orl lprolm nd triolm. Clin Phrmcokinet 9: , Brooks CJW, Gilbert MT: Studies of urinry metbolites of 2-(4-isobutylphenyl) propionic cid by gs-liquid chromtogrphy mss-spectrometry. J Chromtogr 99: , Vesell ES, Penno MB: Assessment of methodc to identify sources of interindividul phrmcokinetic vritions. Clin Phrmcokinet 8:378-49, Lockwood GF, Albert KS, Spunr GJ, Wgner JG: Phrmcokinetics of ibuprofen in mn Plsm protein binding. J Phrmcokinet Biophrm 1 :