naproxen-metabolism, excretion and comparative pharmacokinetics

Scand J Rheumatology, Suppl. 2: 29-36, 1973

NAPROXEN-METABOLISM, EXCRETION AND COMPARATIVE PHARMACO KINE TI CS

Richard Runkel, Enrico Forchielli, Gerhard Boost, Melvin Chaplin, Robert Hill, Hilli Sevelius, Geoffrey Thompson and Eugene Segre

From Syniex Research. Stanford Indusirial Park, Pa10 Alto, California, USA

The importance of absorption, metabolism and pharmacokinetic studies in the development of new drug substances has grown considerably in the last ten years. Drug disposition intelligence has become an essential portion of the total monograph which must be developed. As a result, naproxen has been exposed to an extensive metabolism and pharmacokinetic treatment.

We have surveyed the kinetics of I.V. and orally administered doses in six species including man and these results provided us with plasma half-lives, mode of excretion trends as well as distribution information (Runkel et al., 1972). Urine specimens collected in these experiments were analyzed and detailed metabolic profiles were obtained (Thomp- son & Collins, 1973). Plasma protein binding results provided the basis for understanding some unusual pharmacokinetic behavior (Ellis & Martin, 1971) and finally, a dose-plasma level response study yielded the information necessary for plan- ning long term dosage regimens (Runkel et al., 1973).

This presentation summarizes the results of studies performed in the pursuit of an understanding of naproxen pharmacokinetics in some animals but particularly in man.

RESULTS AND DISCUSSION Fig. 1 shows the naproxen plasma concentration obtained after I.V. and oral administration of a 3 mg/kg radioactive dose in rats. Following 1.V. administration, drug disappearance from the plasma proceeded in two log-linear phases. The first is more rapid and represents largely distribution of the drug from plasma to other body compartments

while the second phase is slower and reflects re- distribution and elimination. Following oral administration plasma concentrations rose to a maximum in 10-20 minutes after which levels decline

la 9[ 8(

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Fig. 1 . Naproxen plasma concentrations in rats following intravenous (0) and oral (0) administration of 3 mg/kg of 'H-labeled naproxen. Runkel et al. (1972).

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Richard Runkel et al.

10 - 9 - 8 - 7. 6 - 5 -

4 -

3l ~

~

l2 24 M 48 TIME lhoursl

Fig. 2. Plasma profile in female volunteer following intravenous administration of 1.2 mg/kg of 3H-labeled naproxen. CI, concentration calculated from plasma radioactivity; 0, concentration of naproxen. Runkel et al. (1972).

at the same rate as the I.V. curve. Plasma half- lives were identical, approximately 5 hours. The extremely rapid appearance in plasma after the oral dose suggests that some gastric absorption has taken place although naproxen is well absorbed from the small intestine.

Oral plasma levels are significantly lower than the I.V. values at all times in the profiles. This is not a result of incomplete absorption since I.V. and oral excretion patterns were identical. Similar I .V./oral differences have been attributed to conjugation in the gut wall or rapid metabolism during the first pass through the liver (Gibaldi & Feld- man, 1972). This behavior was peculiar to the rat so we did not pursue the mechanism further.

Fig. 2 shows the plasma profile in a healthy female volunteer following I .V. administration of 100 mg of "-naproxen. In humans, as in rats,

Scund J Rheurnarology, Suppl2

the I.V. profiles manifest two compartment behavior with the distributive phase ending 2 to 3 hours after administration. Half-lives estimated from the terminal linear phase ranged from 12 to 15 hours.

The circles represent unchanged naproxen concentrations obtained by G.L.C. and the squares are the non-discriminating total radioactivity result. Concentrations by these two methods are identical at all times during the experiment. This shows that unchanged naproxen is the only species present in human plasma following a 100 mg dose. Following seven days of continuous oral dosing and a second I.V. radioactive experiment in the same subject, the plasma pharmacokinetics were identical. We concluded from this result that accommodation to the drug does not occur.

Although species differences in pharmacokinetic parameters is common knowledge we were sur- prised to observe such wide differences in naproxen half-lives. Table I shows the tabulated results of our survey of 6 species. Half-lives were lowest in the rhesus monkey, 2 hours and highest in the dog, 35 hours, these differing by a factor of more than 10. The human half-life is 14 hours, ideal for twice-a-day dosing.

Volumes of distribution provide an index of a drug's affinity to the blood. A low volume of distribution indicates that a large fraction of the drug is held in the central circulatory system. Naproxen has a relatively small volume of distribution, about 10 % of the body weight in humans. Extensive plasma protein binding apparently acts to restrict naproxen largely to the plasma compartment. Inter- species differences in this distribution parameter are not large; the extremes are man 0.09 I/kg and the rodent at 0.18 I/kg.

The tissue distribution of radioactive naproxen 24 hours after I.V. administration of a 3 mg/kg

Table I. Summary of volumes of distribution, V d , and plasma half-life, t t, values (Runkel et al. 1972)

~-

f t (h) Vd (1 /kg) Species MeankS .D. Mean2S.D.

Rat 5.121.8 0.18&0.06 Dog 35.02 11.6 0.12&0.8

Minipig 4.820.8 0.12k0.03 Human 13.922.6 0.09-+0.03

Guinea pig 8.7?2.1 0.12&0.01 Rhesus monkey 1.920.7 0.1020.04

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Naproxen-metabolism 3 1

Table 11. Radioactivity levels in tissues of a rat 24 h after oral administration of 3 mglkg of 3H- labeled naproxen (Runkel et al . , 1972).

Percent of d.p.m./Total d.p.m./g administered

Tissue tissue tissue dose

Spleen 1 050 1390 0.01 Heart 890 680 0.01 Lung 10 010 2 910 0.03 Liver 36 770 2 000 0.12 Kidney 9 160 2 510 0.03 Digestive system 168 500 8 100 0.50 Feces 478 OOO 168 280 1.5

dose in rats is shown in Table 11. These data il- lustrate two important points l ) that very little naproxen lingers in the rat 24 hours after administration and 2) that there was no preferential up- take of naproxen in any of the tissues analyzed. Fecal matter and the digestive system accounted for practically all of the residual radioactivity.

A summary of the mode of excretion of intravenously administered naproxen appears in Table 111. There was a uniform tendency to eliminate naproxen by way of the urine. Only the dog excreted an important portion of the administered dose, 50 %, in the feces suggesting extensive biliary involvement in that species. Humans on the con- trary excreted naproxen almost exclusively in the urine with only 1 % appearing in the feces.

Human metabolism of naproxen determined by analysis of the urinary radioactivity following a 100 mg I.V. dose was found to be relatively simple. The parent structure was altered only by removal of the 6-methoxy group, and by conjugation of the acid function. Fig. 3 shows that 70 % of the ingested dose was eliminated either as unchanged naproxen, 10 %, or as conjugated naproxen, 60 %. This conjugated fraction was comprised of 40 % naproxen glucuronide and 20 % unknown conjugate. Some 28 % of the dose underwent 6-demethyla- tion. As a consequence, 5 % of the dose appeared in the urine as demethylated naproxen, and 22 % as conjugates of demethylated naproxen. These conjugates are further separable into 12 % glucuronide and 11 % unknown conjugate.

Naproxen, administered to man in single oral doses of 100 to 300 mg, is fully absorbed and the dose-plasma level response is linear (Runkel et al., 1972). However, during a highdose tolerance study

we found that the plasma concentrations in subjects who received 250, 400 or 600 mg naproxen t.i.d. no longer conformed to this pattern: mean plasma levels 12 hours after the 600 mg t.i.d. regimen were only 25 % higher than those after 250 mg t.i.d.

These observations were reminiscent of those reported by Brodie et al. (1954), who found that human plasma levels of phenylbutazone failed to increase proportionately with increasing doses but instead tended to level off. To explain this they hypothesized that with the higher doses a larger proportion of the circulating phenylbutazone would not be bound to plasma proteins and would thus be promptly excreted, leading to a plateau in the dose-response curve.

Since naproxen resembles phenylbutazone in hav- ing a strong affhity for serum albumin, we con- sidered a similar mechanism might explain the plateau effect with both drugs. Accordingly, we undertook to define the plasma response curve for an extensive dose range and using tritium labeled naproxen, to uncover the mechanism for this unusual behavior.

Twenty-four healthy informed male volunteers within a narrow range of weight were selected for this study. They were divided into 6 groups of 4, and received doses of 125, 250, 375, 500, 625 and 750 mg, respectively of naproxen in capsule form. The dosage regimen was as follows: (1) a single dose was administered at 8.30 a.m. on day 1 , (2) on days 2, 3, and 4, the same dose was administered twice, once at 8.30 a.m. and once at 8.30 p.m., (3) finally, on day 5 a single administration was given at 8.30 a.m. Blood was drawn at appro- priate times and the plasma was analyzed for naproxen by a G.L.C. method.

Table 111. Mode of excretion of intravenously administered 3H-labeled naproxen (Runkel et al . , 1972)

Percent administered radioactivity excreted

Species Urine Feces

Rat 78 2 Dog 29 50 Guinea pig 89 5 Rhesus monkey 78 1 Minipig 87 1 Human 94 1

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32 Richard Runkel et al.

NAPROXEN O E M E T H Y L A T E O N A P R O X E N

Unknown C o n j u g a t e G l u c u r o n i d e o f Unknown C o n j u g a t e G l u c u r o n i d c o f Naproxen o f Naproxen D e m e t h y l a t e d o f O e n e t h y l a t e d

Naproxen Naproxen

40% 201. 1 2 s 1 1 %

T O T A L - 7 0 % TOTAL - 28:

Fig. 3. Distribution of naproxen metabolites in human urine. Thompson & Collins (1973).

The profiles in Fig. 4 reflect the initial plasma response to a single oral dose, the attaining of the plateau or steady state by 72 hours as a result of the b.i.d. regimen and finally, a second single dose response on day 5 rising from the respective % hour levels. While the 72 hours plasma level of the 250 mg b i d . group is twice that of the 125 mg group, this proportionate response is not main- tained with doses of 375 mg and above. Steady state levels following administration of 500, 625 and 750 mg b.i.d. deviate progressively from the linear and ultimately appear to approach an asymp- totic maximum.

We measured the 0-24 hour areas under the day 1 and day 5 curves and they are plotted against dose, in Fig. 5 . This figure shows the day 1, and the day, area response to the various doses of naproxen. The day 1 regression line starts at the origin, is linear up to 500 mg and the slope of the line is 2 Area Units per mg of drug. Significant deviation from linearity occurred above the 500 mg dose however, and deviation progressed until the area increment between the 750 and 900 mg doses was minimal. The day 5 Areas are higher than day 1 Areas because of residual circulating naproxen.

In an attempt to uncover the mechanism for

TIME

Fig. 4 . Plasma profiles following single oral administration of 125 to 750 rng of naproxen on days I and 5 , with 24-hour levels on intervening days 2. 3, and 4. The points indicate plasma concentration averages of

four subjects. 0, 125 mg; 0, 250 mg; A, 375 mg; W, SO0 mg; A, 625 mg; 0, 750 mg. Runkel et d. (1973).

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Naproxen-metriholism 33

the non-linear area response we planned experiments with radioactive naproxen at two dose levels; one at 250 mg on the linear portion of the area response line, and one at 900 mg which is well into the non-linear segment. The experimental design described earlier was repeated with the addition of urine and stools analysis.

Table IV shows the quantity of isotope recovered during the 96 hours following the day 1 experiment. Most of the radioactivity appears in the urine. Minimal amounts were recovered in the stools for both doses, and these results dupli- cate the excretion pattern we observed earlier following an I.V. dose. We conclude from this result that absorption was complete at both dose levels and that the non-linear plasma response to high naproxen doses was not a result of faulty absorption.

We did, however, find our answer in the urinary clearance data. Fig. 6 shows the relationship of the urinary excretion rate to plasma concentrations measured at the mid-point in the urine collec- tion periods. The solid line is the least squares fit and shows that the relationship is not linear as it should be; but parabolic in shape. The slope of the least squares line, which is total clearance, is plotted in a dashed line and demonstrates how urinary clearance accelerates at high plasma concentrations. Certainly more rapid clearance at high doses would appear to explain the lower than expected area responses we observed.

Because of this clearance phenomenon we stud- ied the plasma protein binding tendencies of naproxen in whole plasma at 22°C in accordance with the methods described by Chaplin (1973). The re-

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600 -

400 -

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I25 250 375 500 625 750 075

DOSE j mgr Naproxrnl

Fig. 5. The dose-area response curve on day 1 (0) and on day 5 (0). The bars indicate the 95% confidence intervals. Runkel et al. (1973)

sults of those binding experiments are shown in Table V. Note that naproxen is very extensively bound to plasma proteins, only 0.4 % free when the total concentration is 23 pglml. Also note that the percent unbound is not constant, but rises as the total concentration is increased; about 1 % free when the total concentration is 150 pg/ml.

Using these binding data we converted the total plasma concentrations shown in Fig. 6 to ultrafiltrate or unbound concentrations. Excretion rates

Table IV. Total, urinary, and fecal 3H recovery following day I radioactive naproxen doses (Runkel et al., 1973)

Dose Percent dose re- Percent dose re- Percent dose re- Subject (mg) covered in urine covered in feces covered total

2 250 88 2 90 5 250 88 2 90 6 250 84 3 87 Average 87 2.3 89 1 900 94 2 97 3 900 I05 0.1 105 4 900 100 2 102

Average 100 1.4 101

Total percent recovered after % hours.

3 - 731861 Rheumatology, Suppl. 2 Scand J Rliertmutdogy, S i ~ p p / 2

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34 Richard R i d e l rt cd.

/ , , , .

. .. . ., .. ,

40 60 80 100 120 140

PLASMA CONCENTRATION (PO 'H.noproxen/ m l l

Frg. 6. Uncorrected urinary clearance of naproxen radioactivity. The points are derived from six subjects three of whom received 250 mg and three 900 mg of 3H- naproxen. - , excretion rate; - - - clearance. Runkel et at. (1973).

were then replotted against the newly derived plasma values in Fig. 7. This figure shows the relationship of the urinary excretion rates to unbound drug concentrations. Now that the correc- tion for plasma protein binding has been made the relationship is linear and urinary clearance is constant. This result suggests that the accelerated clearance seen in Fig. 6 was due largely to saturation of binding sites in the plasma, causing release of greater concentrations of free drug.

Since only unbound drug is available for meta-

Table V . In \*itro plcisriin binding drita in rihole plcismci at 21°C Each value represents the mean 2S.D. from five in- dividuals (Runkel et al., 1973)

Naproxen concentrations (pglml)

Whole plasma Ultrafiltrate rC Free naproxen

23.0r0.6 48.82 1.4 94.8t 1.2 150.2-4.6 194.4- 7.0 273.1-6.6 387.62 11.6 473.5272

0.092 0,002 0.23 -0.04 0.66t0.10 I.43-cO.22 2.05 -0.20 3.93 20.58 7.302 1.07 11.61- 1.42

0.37-tO.04 0.4720.08 0.69-tO.10 0.95-tO.16 1.16?0.14 1.42-0.20 1.9420.22 2.6720.46

80 -

60 -

40 -

ULTRAFILTRATE CONCENTRATION (pq noproxcn / m l )

Fig. 7. Urinary clearance of naproxen radioactivity cor- rected for plasma protein binding effect. The points are derived from six subjects, three of whom received 250 mg and three 900 mg of 3H-naproxen. Runkel et al. (1973).

bolism and renal clearance (Kruger-Thiemer et al., 1965). the effect of high naproxen doses creating larger vulnerable concentrations would be to speed up drug excretion. This in turn results in lower than expected plasma areas.

These data suggest that there is a self-regulatory mechanism which, by virtue of plasma binding site saturation, limits naproxen plasma levels in man and which may well limit toxic effects should an overdose of naproxen be taken. By contrast, with salicylate overdose saturation of metabolizing en- zyme sites decreases clearance (Levy, 1965) and en- courages the accumulation which results in toxicity.

Some guidance for clinical use of naproxen can be obtained from these observations. Since patients given doses of greater than 500 mg twice-a-day over a long period of time, do not develop appre- ciably higher levels than those who receive lower doses. there is probably little advantage to exceed- ing this dose limit in long term administration. However. an initial high loading dose may be indi- cated when rapid establishment of a high plasma level is desired, such as in treatment of acute gout or to achieve analgesia.

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Naproxen-metabolism 35

ACKNOWLEDGEMENTS The authors express their sincere thanks for the techni- cal assistance of Donald Parsons, Louise Gammel Spain, Ralph Magoun, Susan Cobner, Judy Collins and Karla Taylor. The authors wish to thank Dr W. Hafferl of Syntex Research for providing the radioactive com- pound and Dr J. Varady for his statistical treatment of these data.

REFERENCES Brodie, B., Lowman, E., Burns, J., Lee, P., Chenkin, T.,

Goldman, A., Weiner, M. & Steel, J. 1954): Observa- tions on the antirheumatic and physiologic effects of phenylbutazone and some comparisons with cortisone. American Journal of Medicine 16: 18 1.

Chaplin, M. D.: Lowering of plasma concentration of (+)-6-methoxy-a-methyl-2-naphthaleneacetic acid (naproxen) by aspirin in rats. Biochemical Pharmaco- logy, in press.

Ellis, D. & Martin, B. (1971(: The plasma protein binding properties of a new non-steroidal anti-inflamma- tory agent. Federation Proceedings 30: 864.

Gibaldi, M. & Feldman, S. (1972): Route of administration and drug metabolism. European Journal of Pharmacology 19: 323.

Kruger-Thiemer, E., Diller, W. & Bunger, P. (1965): Pharmacokinetic models requiring protein binding of drugs. Antimicrobial Agents and Chemotherapy 183.

Levy, G. (1%5): Pharrnacokinetis of salicylate elimination in man. Journal of Pharmaceutical Sciences 54: 959.

Runkel, R., Chaplin, M., Boost, G., Segre, E. & Forchi- elli, E. (1972): Absorption, distribution, metabolism and excretion of naproxen in various laboratory animals and human subjects. Journal of Pharmaceutical Sciences 61: 703.

Runkel, R., Forchielli, E., Sevelius, H., Chaplin, M. & Segre, E. (1973): Non-linear plasma level response to high doses of naproxen. Submitted to Clinical Pharma- cology and Therapeutics.

Thompson, G. & Collins, J. (1973): Urinary metabolic profiles for choosing test animals for chronic toxicity studies: application to naproxen. Journal of Pharma- ceutical Sciences 62.

NAPROXEN - STOFFWECHSEL, AUSSCHEIDUNG UND VERGLEICHENDE PHARMAKOKINETIK

Absorption, Verteilung, Metabolismus und Aus- scheidung von Naproxen, wurden bei verschiedenen Tierarten und Menschen untersucht. Blut-, Urin- und Stuhlanalysen wurden an Proben durchge- fuhrt, die zu bestimmten Zeiten nach intravenosen oder oralen Dosen von :jH - Naproxen erhalten wurden. lm Blut wird es mit einer Halbwertszeit von 2-35 Std. auf verschiedene Weise abgebaut. Im Menschen liegt die Halbwertszeit bei 14 Std. Durch weitreichende Protein- Plasma-Bindung wurde ein grosser Teil des Mittels im Blut fest- gehalten und zeigte keine ungewohliche Aftinitat zu anderen Geweben. Beim Menschen wird Naproxen hauptsachlich im Urin ausgeschieden, wovon 70 %

unverandertes Naproxen oder Naproxenkonjugate waren, 28 % entweder demethyliertes Naproxen oder dessen Konjugate. Die Veranderung des Plas- maniveaus bei einer Dosierung von 125-900 mg Naproxen 2maI taglich, wurde untersucht und ergab eine lineare Zunahme bis zu 500 rng 2mal taglich, mit Abflachung der Kurve bei hoheren Dosen. Eine beschleunigte Nierenclearance bei hohen Do- sen wurde festgestellt, hervorgerufen durch eine Sattigung der Plasmaprotein-Bindungsstellen. Dies konnte fur das beobachtete Abflachen der Kurve verantwortlich sein. Ein wertvoller klinischer Hin- weis wurde mit der Aufdeckung dieses Selbstregula- tions-Mechanismus gewonnen.

NAPROXENE - MfiTABOLISME, EXCRfiTION ET PHARMACOCINfiTIQUE COMPARfiE

Des etudes comparees sur I’absorption, la reparti- voie intraveineuse ou orale de doses de naproxene tion, le metabolisrne et I’excrttion du naproxtne tritie. On a constate que cette substance est ab- ont CtC effectuees dans differentes esptces, y com- sorbee rapidement et completement par I’appareil pris chez l’homme. On a analyst5 le sang, les urines digestif, et, qu’une fois dans le sang, elle est eli- et les ftces, a partir d’echantillons recueilles minee a un rythme variant d’une esptce a des moments determines, aprts administration par i’autre, la periode biologique s’echelonnant de 2 a

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36 Ricliurd Rirnkel et ul.

35 heures. Chez I’homme. la periode correspon- dante est de 14 heures. Une proportion importante du compose se fixant sur les proteines du plasma est retenue dans le sang et ne manifeste aucune affinite particuliere pour les autres tissues. Le naproxene est elimine essentiellement par les urines; 70 % du produit se retrouve tel quel ou en combinaison, et 28 5% sous une forme demethylee. soit seule, soit conjuguee avec un autre corps. Une Ctude des reactions au niveau du plasma. apres administration, deux fois par jour, de doses allant de 125 a 900 mg. a montre que les zones de con-

centration du naproxene dans le plasma ont ten- dance a augmenter de fagon lineaire jusqu’a une prise biquotidienne de 500 mg. mais qu’elles semblent plafonner pour les doses plus elevees. L’ explication la plus vraisemblable de ce phenomene serait qu’a fortes doses la clearance renale se fait a un rythme accelere, par suite de la saturation des points de fixation sur les proteines du plasma. La decouverte de ce mecanisme d’auto- regulation est d’un grand inter&t pour la pratique clinique.

NAPROXEN: ESTUDIOS SOBRE METABOLISMO, EXCRECION Y FARMACOCINETICA COMPARADA

Se estudiaron comparativamente en varias especies. incluso el hombre. la absorcion. distribucion, metabolismo y excrecion del naproxen. Se efectuaron analisis de sangre, orina y heces en muestras ob- tenidas a intervalos determinados despues de la administracion intravenosa u oral de “H-naproxen. Se observo que el naproxen se absorbia rapida y totalmente por via oral y que. una vez en la sangre. era eliminado con una vida media de 2 a 35 horas en las distintas especies. La vida media en el hombre fue de 14 horas. Debido a su gran capacidad para fijarse a las proteinas plasmaticas. una importante fraccion del farrnaco perrnanecio en la sangre y sin afinidad especial para otros tejidos. En el hombre. el naproxen se elimina principalmente por la orina; el 70 % como el farmaco sin modificar o en con-

jugados del naproxen, mientras que el 28 % es naproxen desmetilado o su conjugado. Un estudio para medir la concentracion plasmatica despues de administrar dosis de 125 a 900 mg, dos veces al dia. mostro que 10s niveles plasmaticos de naproxen aumentaban linealmente hasta la dosis de 500 mg dos veces diarias, pero tendian a estabilizarse con dosis superiores. La explica- cion mas probable de ese efecto de estabilizacion parece ser el increment0 de la depuracion renal por las dosis altas a consecuencia de la satura- cion de 10s puntos de enlace de las proteinas piasmaticas. Este estudio proporciono orientacio- nes clinicas, valiosas gracias al descubrimiento de ese mecanismo de autorregulacion.

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naproxen-metabolism, excretion and comparative pharmacokinetics

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