14 BRIEF REPORT IBUPROFEN KINETICS IN PATIENTS ITH RENAL INSUFFICIENCY HO ARE RECEIVING MAINTENANCE HEMODIALY SIS HERMANN R. OCHS, DAVID J. GREENBLATT, and BIRGITT VERBURGOCHS Ibuprofen is a nonsteroidal antiinflammatory agent widely presribed for the treatment of pain and inflammatory disorders (1). The major metaboli pathway of ibuprofen involves hydroxylation by hepati oxidative mehanisms, followed by urinary exretion of gluuronide onjugates (2,). Previous studies of drugs of this lass have indiated that renal insuffiieny may alter their kineti profile of absorption, distribution, elimination, learane, and plasma protein binding (8). This is of onsiderable importane, sine many patients with renal insuffiieny may require analgesi treatment. In the present study, we evaluated the kinetis and protein binding of a single oral dose of ibuprofen in a series of patients with renal insuffiieny requiring longterm maintenane hemodialysis. Patients and methods. Eight male patients, aged 248, partiipated in this study after giving their informed onsent. All had hroni renal insuffiieny and were reeiving maintenane hemodialysis 2 or times weekly. Their mean serum reatinine onentration was 1.6 mg/loo ml. Patients were reeiving other From the Mediinishe Universitatsklinik, University of Bonn, est Germany, and the Division of Clinial Pharmaology, TuftsNew England Medial Center, Boston, Massahusetts. Supported in part by grant OC 1/64 from Deutshe Forshungsgemeinshaft and by grant MH422 from the USPHS. Prof. Dr. med. Hermann R. Ohs: Professor, University of Bonn (urrent address: Marienkrankenhaus, Soest, est Germany); David J. Greenblatt, MD: Professor of Psyhiatry and Mediine, TuftsNew England Medial Center; Dr. med Birgitt VerburgOhs: Anesthesiologist, University of Bonn (urrent address: Soest, est Germany). Address reprint requests to Prof. Dr. med. Hermann R. Ohs, Marienkrankenhaus, idumgasse 5, D477 Soest, est Germany. Submitted for publiation Deember 27, 1984; aepted in revised form May 22, 1985. mediations for the treatment of ompliations of renal failure; these inluded: hypophosphatemi agents, antihypertensive drugs, vitamin supplements, and digitalis glyosides. However, all patients were linially stable and without evidene of ative interurrent illness. Ten healthy male volunteers, aged 2147, also partiipated in the study, serving as agemathed ontrols. Control subjets were ative, ambulatory adults with no evidene of disease and were reeiving no other mediations at the time of the study. After an overnight fast, patients reeived a single 6mg oral dose of ibuprofen (Dolorgiet GmbH, St. Augustin, est Germany) with 12 ml of water. They ontinued to fast until hours after drug administration. Immediately after ibuprofen was given, they began their routine hemodialysis treatment, whih lasted for the next 46 hours. Venous blood samples were drawn into additivefree tubes prior to ibuprofen dosage and at the following postdosage times:.5, 1, 2,, 4, 6, 8, 12, and 16 hours. Samples were allowed to lot, and the serum was separated and froen until the time of assay. Control subjets likewise reeived a single 6mg oral dose of ibuprofen after an overnight fast, and they ontinued to fast until hours after dosage. Venous blood samples were drawn prior to ibuprofen administration and at the following postdosage times:.25,.5,.75, 1, 1.5, 2, 2.5,, 4, 6, 8, 1, 12, and 16 hours. Serum was separated and froen until the time of assay. Conentrations of total (free plus bound) ibuprofen in all samples were determined by high performane liquid hromatography (9). For eah subjet, the extent of ibuprofen binding to serum protein Arthritis and Rheumatism, Vol. 28, No. 12 (Deember 1985)
BRIEF REPORTS 14 1 Table 1. Ibuprofen kinetis in ontrol subjets and patients with renal insuffiieny reeiving maintenane hemodialysis* Subiet harateristis Age eight (kg) Serum reatinine (mg/1 ml) Control Renal subjets patients Value of (n = 1) (n = 8) Student s tt.4 2 2.7 74. t..9 f.4.8 f.2 61.8 t.5 1.6 f.9.9 (NS) 2.65 (P <.2) 16.5 (P <.1) Kinetis of total ibuprofen Peak serum level (dml) Time of peak (hours after dose) Elimination halflife (hours) Apparent volume of distribution (liters) (liters/kg) Oral learane (ml/minute) (ml/minute/kg) 49.1 f.1 1.2 f.8 1.95?.9 11.6 t.45.16 t.1 69.6 2 2.7.95 t.5 2.2 t 4.1 2.8 t.7 2.5?.9 1.5 t 2.12.22?. 95.1 t 24 1.52?.7.6 (P <.1) 2. (P <.5).28 (NS) Kinetis of unbound ibuprofen Free fration (% unbound) Peak free serum level (CLg/ml) Free volume of distribution (literdkg) Free learane (ml/minute/kg) 1.7 t.4.52 t.4 15. t 1. 9.8 & 6.7 * Values are mean f SE. Total ibuprofen = free plus bound. t NS = not signifiant.8?.67.82 t.9 9. t 1.9 62.6 f 18.1.5 (P <.1).6 (P <.1) 2.96 (P <.1) 1.59 (NS) was determined from a single pooled sample. The free fration was determined after addition of 14Clabeled ibuprofen (15 nci/ml) to dupliate 1ml serum aliquots, and after equilibrium dialysis for a period of 6 hours (1,ll). Ibuprofen binding was onentrationindependent over the range of onentrations enountered in the present study. For eah subjet, the apparent elimination halflife of ibuprofen was determined from the slope (beta) of the terminal loglinear phase of the plasma onentration urve. Area under the urve until the final detetable onentration was determined by the trapeoidal method. To this value was added the residual areal extrapolated to infinity, alulated as the final onentration divided by beta, yielding total area under the urve. Assuming 1% systemi availability of the orally administered dose, apparent oral learane of ibuprofen was alulated as dosehotal area under the urve and volume of distribution as learanebeta. To orret for individual differenes in free fration (12,1), values of volume of distribution and learane for total (free plus bound) ibuprofen were divided by individual values of free fration, yielding ibuprofen unbound volume of distribution and ibuprofen free learane. Differenes between ontrol subjets and patients were evaluated by Student s independent rtest. Results. Control subjets and patients who had renal failure were well mathed for age (Table 1). Renal failure patients had signifiantly lower body weight than did the ontrol subjets. Figure 1 shows representative serum onentration urves. Based on total (free plus bound) ibuprofen serum onentrations, peak levels were lower and were attained later in patients with renal failure ompared with the ontrols (Table 1). Elimination halflife of ibuprofen was essentially idential between groups (Figure 2). Apparent volume of distribution and oral
142 BRIEF REPORTS v) \ \ CONTROL 5 t.2l,,,,,,,, ; L I 2 4 6 8 12 I6 2 4 6 8 12 16 HOURS AFTER DOSE Figure 1. Serum ibuprofen onentrations in representative healthy ontrol subjets (left panel) and patients with renal insufiieny reeiving maintenane hemodialysis (right panel), after a single 6mg oral dose. learane of ibuprofen tended to be higher in renal failure patients ompared with ontrols, although the differenes did not reah statistial signifiane. Ibuprofen was less extensively bound to serum protein in patients with renal failure. The mean free fration was.8% in the patients, ompared with 1.7% in the ontrols (P <.1). The redued serum protein binding of ibuprofen importantly altered the interpretation of kineti variables (1217). After orretion for individual values of protein binding, volume of distribution of unbound ibuprofen was signifiantly smaller in renal failure patients ompared with ontrols, and peak serum levels of unbound ibuprofen were signifiantly higher. Free learane of ibuprofen in 6 of the 8 patients was lower than that in any ontrols, but the overall differene between groups did not reah statistial signifiane (Table 1 and Figure 2). Disussion. Renal insuffiieny an alter the pharmaokineti profile of a number of drugs (18). Suh differenes have been found among subjets in many studies of nonsteroidal antiinflammatory agents (8). Results of the present study of dialysisdependent patients with renal igsuffiieny suggested that ibuprofen was more slowly absorbed in the patients ompared with the ontrols, based on a more 1 ; LL J 1 2! 4 G r J 1 $ o CONTRC 1: R NAL 8 7 2 6 5 5 m 4 1; RENAL P s > 25. L p 2 G a I+ I v, LL A r l 9 kl! 5 L. :. CON TRO p 14 s. 81 I6 E 12 1. E r loo 8 : a.4 6 6 2o i CONTRO Figure 2. Individual and mean (kse) values of ibuprofen elimination halflife, free fration in serum, free volume of distribution, and free learane in 1 healthy ontrol subjets and 8 patients with renal insuffiieny reeiving maintenane hemodialysis, after a single 6mg oral dose. See Table 1 for statistial analysis.
BRIEF REPORTS 14 than twofold prolongation of the time of peak serum onentration following a single oral dose. Sine the absorption phase of the serum onentration profile during the first several hours after ibuprofen administration oinided with the dialysis proedure, the slower absorption of ibuprofen among renal failure patients might be explained by the hemodynami ongsequenes of dialysis, whih an ause redued gastrointestinal blood flow. Comparison of volume of distribution and learane of ibuprofen based on total (free plus bound) serum onentrations suggested no signifiant differene between ontrols and patients; if anything, there was slightly more extensive distribution and higher values of oral learane in the patients. However, as is true of many other drugs, ibuprofen had greatly reduled serum protein binding values in the patients with renal failure. The mean free fration was >% among patients, ompared with a mean value of 1.7% in heallthy ontrols. This inrease in free fration in and of itself would not alter the kineti profile of the pharmaologially ative unbound drug, nor would it alter the linial effet of ibuprofen (12). On the other hand, binding hanges have an important influene on the interpretation of pharmaokineti variables based on lotal (free plus bound) serum levels (1219). After orretion for individual differenes in free fration, peak onentrations of unbound ibuprofen in serum were signifiantly higher in patients than in ontrols, and volume of distribution of unbound ibuprofen was signifiantly less (patients versus ontrols). In 6 of the 8 dialysis patients, ibuprofen free learane was lower than it was in all of the ontrol sub.jets. The mean free learane value was also lower in dialysis patients than in ontrols, although the overall differene between groups was not statistially signifiant. Thus, distribution and learane are, if anything, redued in dialysisdependent patients with renal insuffiieny: The opposite onlusions might have been drawn if the serum onentrations of total ibuprofen had been onsidered alone. This emphasies the need for orretion of kineti variables for individual values of free fration during pharmaokineti studies of disease states whih might be assoiated with altered drug binding to plasma protein (1219). Although free learane of ibuprofen among pati~ents overall was not signifiantly different from that of the ontrols, there were wide variations in free learane among the patients, with low values in 6 of theim. e did not atually evaluate the extent of ibuprofen aumulation during longterm therapy in the patients. However, the low free learane values in many of the patients suggest that suh individuals ould be suseptible to exess aumulation of free ibuprofen during multiple dosage, and that a need for a redued dosage of ibuprofen (by 255%) ould be antiipated. Further linial and pharmaokineti studies during multiple dosage are needed in order to validate this reommendation. It must be emphasied that all patients in our study were being treated with other drugs, and that part of the study was arried out during the hemodialysis proedure. Thus, it is not possible to tell whether differenes between ontrol subjets and patients were due to the underlying disease, to the mediations used to treat the disease, or to the atual dialysis proedure. Dialysisdependent patients with renal failure atually spend a small fration (< 1%) of their time undergoing dialysis, and it is not neessarily true that the observed alterations in ibuprofen kinetis would apply to the interdialysis interval. Removal of ibuprofen by the dialysis proedure appears to be minimal (2), suggesting that dialysis itself probably does not importantly enhane learape of free drug. Renal insuffiieny and/or onurrent mediations an be assoiated with redued learane of drugs whose major route of learane is hepati biotransformation, whether or not drug learane is measured during dialysis itself (2124). Aknowledgments. e are grateful for the assistane of Rita Matlis and Jerold S. Harmat. 1. 2.. 4. 5. 6. 7. REFERENCES Kantor TG: Ibuprofen. Ann Intern Med 91:877882, 1979 Mills RFN, Adam SS, Cliffe EE, Dikenson, Niholson JS: The metabolism of ibuprofen. Xenobiotia 589598, 197 Verbeek RK, Blakburn JL, Loewen GR: Clinial pharmaokinetis of nonsteroidal antiinflammatory drugs. Clin Pharmaokinet 8:2971, 198 Enderle C, Held H: Elimination and serum protein binding of phenylbutaone id patients with renal insuffiieny. Clin Nephrol6:889, 1976 Aronoff OR, Oawa T, DeSante KA, Nash JF, Ridolfo AS: Benoxaprofen kinetis in renal impairment. Clin Pharmaol Ther 2: 19194, 1982 Anttila M, Haataja M, Kasanen A: Pharmaokinetis of naproxen in subjets with normal and impaired renal funtion. Eur J Clin Pharmaol 18:26268, 198 Rogers HJ, Savitsky JP, Glenn B, Spetor RG: Kinetis of single doses of fenbufen in patients with renal insuffiieny. Clin Pharmaol Ther 29:748, 1981
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