Acetaminophen

Bioavailability Monograph

As research and study regarding the bioavailability of drug products continue, additional information will be made available adding to and/or alter!ng the information and conclusions contained in this monograph. Drug manufacturers and others who conduct bioavailability studies of drug products are encouraged to submit their results immediately to APhA. Monographs will be revised and updated periodically to reflect new information, and when necessary special announcements regarding new data will appear in this Journal.

Acetaminophen is a nonsalicylate analgesic / antipyretic. In recent years, its popularity as an "aspirin substitute" has increased to the point that the drug is now available from many sources in several dosage forms. Acetaminophen was described as having low or negligible risk potential for biological inequivalence by an ad hoc committee of the APhA Academy of Pharmacy Practice and the APhA Academy of Pharmaceutical Sciences. 1 The APhA Academy of Pharmaceutical Sciences also included acetaminophen on a list of drugs that was considered to have the least potential for bioavailability differences. 2 Available data suggest that the drug is absorbed completely from oral dosage forms. Product formulation or other factors such as food in the stomach influence the absorption rate and possibly the speed of therapeutic onset. The Drug Entity

General Characteristics-Oral administration of acetaminophen solutions to fasting subjects results in rapid and complete absorption 3 with peak plasma levels occurring in 20-45 minutes. The rate, but not the extent, of acetaminophen absorption is affected by gastric emptying time. Delayed gastric emptying (due to food) results in lower peak plasma levels at later times (1-2 hours) . Acetaminophen from well-formulated tablets is absorbed as rapidly as from solutions. However, some solid dosage forms result in slower absorption but not a reduced extent of absorption. Acetaminophen is metabolized by the liver. It has been estimated that approximately 17 percent of a dose is metabolized in its first pass through the liver Vol. NS 17, No.8, August 1977

Acetaminophen

following oral absorption. 4 The half-life of acetaminophen is approximately 3 hours. Essentially all of an absorbed dose is excreted in urine as acetaminophen glucuronide (55-75 percent) , acetaminophen sulfate (20-40 percent) and unchanged acetaminophen (2-5 percent) ; other metabolites are present in trace amounts. The formation rate of acetaminophen glucuronide is more rapid (t 112 4-5 hours) than that of acetaminophen sulfate (t 112 = 8-1 0 hours) .5

=

However, both metabolites are excreted rapidly (acetaminophen sulfate, t1l2 = 0.5-0.9 hour; acetaminophen glucuronide, t1/2 = 0.7-1.4 hours). Renal excretion of unchanged acetaminophen is slow (t1/2 = 50-70 hours).5 The proportions of the two main metabolites in urine vary widely among subjects and doses because of individual differences and because sulfate formation can be saturated at 1-2 g doses. Plasma protein binding of acetaminophen is negligible at low concentrations but increases with increaSing concentration. 4 Protein binding does not playa significant role in acetaminophen bioavailability or disposition. Combination Products-Numerous products contain acetaminophen in combination with phenacetin, aspirin, salicylamide, codeine, antihistamines or caffeine. Unfortunately, no data are available on acetaminophen bioavailability from such combinations or on drug interactions between acetaminophen and other drugs, although interactions are possible. For example, acetaminophen is frequently administered with salicylamide, which inhibits acetaminophen metabolism. Physical Properties-The reported solubilities of acetaminophen (mol. wt. 151.16) in water are: 20 ° , 11.3 mg/ml;6 25 ° ,13.85 mg/ml;7 37 ° , ~20 mg/ml;8 and 100°, ~52 mg/ml.9 Acetaminophen is a weak acid and its saturated aqueous solution has a pH of 5.3-6.5 at 25 °. 10 The reported pKa values for acetaminophen range from 9.0 11 to 9.5. 12 Acetaminophen is slightly light sensitive in solution. 9 Dry, pure acetaminophen is very stable up to at least 45 0 . Humid conditions may cause hydrolYSiS to p-aminophenol which is also oxidized as indicated by a color change from pink to black. 13 Acetaminophen degradation in aqueous solution appears to be acid catalyzed and base catalyzed. 14, 15 Maximum stability is seen

at pH 5-6. 14 USP XIX requires that acetaminophen tablets diSintegrate in 30 minutes. The dissolution rate of the drug in compressed tablets is approximately 2.7 mg/min.16 Analytical Methods

The hydrolysis of acetaminophen to p-aminophenol is the basis for most acetaminophen analytical techniques. Initially, a colorimetric technique for paminophenol derived from acetaminophen in plasma was reported, 17 However, substantially different results were obtained when plasma was hydrolyzed directly followed by analysis for p-aminophenol, and when acetaminophen was first extracted from plasma followed by subsequent hydrolYSis and analysiS. In the first case, the glucuronide and, to some extent, the sulfate metabolites of acetaminophen, as well as unchanged acetaminophen, were hydrolyzed to p-aminophenol. In the second case, only acetaminophen was analyzed since the two polar metabolites were not extracted. This problem was confirmed 18 by showing that the apparent acetaminophen levels from a hydrolyzed plasma sample were the same as those obtained from an identical but non hydrolyzed plasma sample which had been appropriately incubated with a mixture of glucuronidase and sulfatase enzymes. One colorimetric technique 19 is used widely for analYSis of total (free plus conjugated) acetaminophen in urine. Free acetaminophen may be analyzed directly in either plasma or urine using a thin-layer chromatographic (TLC) techniqueS or gas-liquid chromatographic (GLC) methods. 20 ,21 The TLC technique is less quantitative than GLC or the colorimetric procedures. The primary advantage of GLC over the colorimetric procedures is increased sensitivity. However, two recent high-pressure liquid chromatographic methods22 ,23 are rapid, specific and sensitive determinations of acetaminophen in biological fluids and are expected to enjoy increased use. One should exercise caution when comparing acetaminophen plasma or urine data obtained from different studies unless the analytical procedures were the same. One study may report only unchanged drug while another may analyze unchanged plus conjugated drug and refer to this as total acetaminophen . 517

Acetaminophen

Bioavailability

Literature Survey and EvaluationThe bioavailability of acetaminophen in six different tablet dosage forms, an elixir and an aqueous solution control was evaluated using 10 subjects in a crossover design. 3 Blood levels and urine levels of acetaminophen plus its metabolites were determined. No significant difference was found among the dosage forms. Differences among individuals were the dominant variable. The mean, overall elimination half-life of acetaminophen in plasma was 3 hours (range 2.52-3.62 hours). The mean peak plasma level occurred at 73 minutes (range 55-96 minutes). There appeared to be minor (nonstatistical) differences in absorption from the different dosage forms, but these were not expected to affect the analgesic efficacy. The equality of the liquid and solid dosage forms strongly suggests that dissolution is not the rate-determining step in the absorption of acetaminophen from well-formulated solid (tablet) dosage forms. The effect of stomach emptying time on the rate and extent of acetaminophen absorption was evaluated using commercial dosage forms.24 Four male subjects were used in a two-way crossover design to compare the bioavailability of acetaminophen given on an empty stomach (with 200 ml of water) to that observed when the drug was taken following a high carbohydrate breakfast. Absorption following overnight fasting was up to five times faster than when the drug was given after the meal; however, the extent of absorption was the same. When the subjects had fasted, the time for peak plasma drug levels occurred at or before 20 minutes (20 minutes following dosing was the time of the earliest blood sample) . Following breakfast, the average peak time was 90 minutes (range 40-120 minutes) . Clearly, stomach emptying time is a major variable in determining the rate, but not the extent, of acetaminophen absorption. Although a well-formulated acetaminophen tablet is apparently absorbed at the same rate as a control solution, acetaminophen from soft gelatin capsules was reported to be absorbed more slowly.25 In another study,26 a regular tablet formulation (Panadol, Winthrop Laboratories) was absorbed more slowly

than an effervescent tablet (Panaseltzer, Wonder Ltd.) . Peak blood levels with the regular tablet averaged 90 minutes whereas peak levels with the effervescent tablet occurred prior to 30 minutes. The subjects were fasted for at least 9 hours prior to the study. This tablet may be an example of a formulation for which dissolution was the rate-determining step in absorption. In Vivo Versus In Vitro Testing-It seems clear that if the acetaminophen absorption rate from some tablet formulations is the same as that from aqueous solutions, dissolution is not the rate-determining step. Given this, measures of the in vitro dissolution rates for such formulations should not be expected to correlate with in vivo absorption rates. It follows that differences in in vitro dissolution rates should not suggest differences in absorption rates. Rectal Absorptiof}-The availability of acetaminophen suppositories has prompted a limited number of studies on the rectal absorption of acetaminophen. The dielectric constant of the vehicle had a direct effect on both the rate and extent of acetaminophen absorption. 27 A vehicle with a dielectric constant consistent with high acetaminophen solubility provided less absorption than a vehicle with a dielectric constant consistent with low solubility. These findings were later confirmed 28 by showing that the rectal bioavailability of acetaminophen in polyethylene glycol 400 was less than that from polyethylene glycol 6000.

reduced absorption rates and presumably a delayed therapeutic onset. Criteria for Bioavailability Tests

The following criteria should be used in designing or evaluating bioavailability studies of acetaminophen tablets. 1. A two-way crossover study design should be employed. 2. The tested tablets should be compared against the same dose of an oral solution. 3. A minimum of six subjects of the same sex and closely matched in weight and age should be used. 4. Each subject should be within normal limits regarding kidney and liver functions. 5. Subjects should be fasted overnight. 6. Seven days should separate the crossover administrations. 7. Blood samples should be taken at 20, 30, 60, 120, 240 and 480 minutes. Information Available From Suppliers

Correlations between blood acetaminophen levels and therapeutic response are not available. The available data indicate that the drug is essentially completely absorbed from the tested oral dosage forms. However, the absorption rate is probably the more important therapeutic parameter. A rapid rise to therapeutic levels would be preferred. As discussed, differences between individuals and differences in individual stomach emptying times can dominate over formulation variables in governing the absorption rate of acetaminophen from liquids and well-formulated tablets. A maximum absorption rate with peak levels prior to 30 minutes appears to be obtained when acetaminophen is taken with water following fasting. Dosing shortly before or after a meal results in

Eighty-one manufacturers and distributors of acetaminophen products were contacted and asked to supply bioavailability information on their acetaminophen tablets. The following did not respond: Abbott Laboratories American Quinine A VP Pharmaceuticals Blue Line Chemical Bolar Pharmaceutical Bowman Pharmaceuticals Carnrick Laboratories Carr Drug Company H. R. Cenci Central Pharmacal Chase Chemical Chromalloy Pharmaceuticals City Chemical Otis Clapp CMC.-Consolidated Midland J. Davis Dome Laboratories Paul B. Elder Fellows-Testagar Ferndale Laboratories and Surgical Gotham Pharmaceutical Grail Corp. G & W Laboratories Don Hall Laboratories Jenkins Laboratories Kay Pharmacal Kenyon Drug

518

Journal of the American Pharmaceutical Association

Clinical Significance

Ketcham Laboratories C. F. Kirk Laboratories Kirkman Laboratories Lannett Lemmon Pharmacal Eli Lilly Medical Chemicals Medics Pharmaceutical Mylan Pharmaceuticals J. R. Nevin Palmedi'c o Parke-Davis Premo Pharmaceutical Laboratories Purepac Pharmaceutical Raway Pharmacal Reid-Provident Laboratories Reiss-Williams Co. Richlyn Liboratories Rondex Laboratories Savage Laboratories Scrip Stanlabs Sutliff & Case Towne, Paulsen Tutag Pharmaceuticals Upsher-Smith Laboratories Ulmer Pharmacal Vita-Fore Products Vitarine Webcon pharmaceuticals Westerfield Laboratories West-ward

The following companies indicated that they manufacture and supply acetaminophen products; in vitro dissolution data Were supplied but no bioavailability data were proVided. Mead Johnson Norwich Pharmacal Pharmaceutical Associates, Inc. (liquid formulations only) Philips Roxane Labs, Inc. Stayner Dooner Laboratories and Bell Pharmacal responded as suppliers, but the manufacturers were not indicated. No bioavailability data were provided. Companies Providing Bioavailability Data

The following companies manufacture acetaminophen tablets and provided data from detailed bioavailabilify studies. Dow Chemical McNeil Laboratories Smith Kline and French Laboratories E. R. Squibb arid Sons

Figure 1. 36 33

Whitewo~th

Winsale brug Zenith Laboratories Of the 81 suppliers and/or manufacturers contacted, the following responded, indicating that they were suppliers. The corresponding' ma[)ufacturer is listed. No bioavailability data were supplied. Supplier

Arcum Pharmaceutical Amid Laboratories Coast Laboratories Columbia Medical H. L. Moore Drug Exchange

Robinson Laboratory Sheraton Laboratories

E 27 0; ~ 24 c

1?Q.

g

'E

Vol. NS 17, No.8, August 1977

21 18

~ 15 ()

«

12 9

Ma n,u fa c turer

Zenith Laboratories Premo Pharmaceuticals Rondex Laboratories J. Davis Zenith Laboratories, Dunburyand Bolar Pharmaceutical Mylan Pharmaceuticals Chromalloy Pharmaceuticals and Chase Chemical

Linear plots of acetaminophen plus metabolite serum levels versus time following oral administration of 650 mg of acetaminophen in combination with 40 mg of phenylephrine hydrochloride to nine fasted subjects. The upper and lower curves represent the range for the mean ± 1 SO. The solid curves are for a reference solution (Dow C-1482) . The dashed curves are for Singlet tablets (Dow C- 1466). The analytical procedure measured both unchanged and metabolized acetaminophen. The subjects ranged in age from 21 to 30 years and in weight from 59.9 to 99. 7 kg. This study was performed by Dow.

. - . Dow liquid 0--0 Dow tablet

30

The blood level data provided by Dow, McNeil and Squibb are shown in Figures 1-5. Fasted subjects were used in all cases. In each case, a range is shown that represents the mean plasma concentration ± 1 So. In each case, different ana-: Iytical procedures were used. The reported acetaminophen levels include metabolites in Figures 1-3. The levels in Figures 4 and 5 are for acetaminophen alone. Relative drug levels should not be compared between figures. However, peak times, a measure of the absorption rate, can be compared among the figures. The range for 1 SO illustrates the between-subject variation . The Dow tablet (Figure 1) appears to have a slower absorption when compared to the Dow liquid and the other tablets. Stomach emptying should not have been a factor since the subjects fasted for 10 hours prior to dosing. Nowever, the data are complicated by the modified colorimetric analytical procedure which apparently

6 3

2

3

Time (hours)

Figure 2. ::::::::-

6

E

0;

~ c

4

Q)

..c:

Q.

3

0

,~

E ro ill ()

2

«

3 Time (hours)

4

5

Linear plots of acetaminophen plus metabolite blood levels versus time following oral administration of 240 mg of drug to 15 fasted subjects, each given Valadol Liquid (Squibb) (solid curves) , Acetaminophen Elixir (McNeil) (dashed curves) and Valadol Chewable Tablets (Squibb) (dotted curves) . In each case, the upper and lower curves represent the range for the mean ± 1 SO. The subjects ' ages and weights and the various product lot numbers were not provided. The analytical procedure measured unchanged and metabolized acetaminophen. This study was performed by Squibb.

Acetaminophen

analyzed for both acetaminophen and its metabolites in plasma. The Dow tablet was not compared to any of the other tablets in this study. The data in Figure 4 were supplied ·corrected for the variations in subject weights. The subjects reported in Figure 3a ranged from 69.3 to 94.7 kg. The range in these data was substantially re-

duced (Figure 3b) when the plasma levels were corrected to a constant weight of 70 kg, but this correction did not alter the equivalency of the products. Correction of plasma levels for differences in subject weight is valid when the apparent volume of distribution of acetaminophen is assumed to be directly proportional to body weight and the same dose is given

Figure 3.

Figure 4. 0--0

a. :=:-

E

Squ ibb tablet

16

~

I i:; .~, " ~

12

(l)

~

L

0..

o c

E co

Q)

u

<{

co

Q)

3 b. :=:-

E

16

12

(l)

L

0.. 0

c

·E

/e_~~-o Squ ibb tablet

,,0-- -

01

~ c

<{

J•\ ,\:\

~

10 9

4

U I.,

3 L

2 ~I

.................. ~

. i

4

3

5

Time (hours)

Linear plots of acetaminophen plus metabolite blood levels versus time following oral administration of 650 mg of drug to eight fasted subjects, each given McNeil (solid curves) and Squibb (dashed curves) acetaminophen tablets. In each case, the upper and lower curves represent the range for the mean ± 1 SO. The product lot numbers were not provided. Key: (a) raw data, uncorrected for weight differences (range 59.9-92.4 kg) . (b) the data in (a) were corrected to 650 mg/70 kg to illustrate the reduced range when subject weight is considered. Similar data were obtained in the crossover study. The analytical procedure measured unchanged and metabolized acetaminophen. This study was performed by Squibb.

E 8

.- . Tylenol Datril

~ c 6 (l)

L

0..

0 .~

E u

"~~~e_ '" ===----

2

"

---8

3

-- 0

~.

4

5

~"

.~_

-I

3

6

520

. 4

pl',,--,, ~" -.. . , ""'-

,

5

6

0- - 0 Tyleno l tab lets

,e

t

"""-i

. - . SK-APAP tab lets

~"

Time (hou rs)

Linear plots of plasma acetaminophen levels versus time following oral administration of 650 mg of drug to 18 fasted subjects, each given Tylenol (McNeil) and oatril (Bristol-Myers) tablets. In each case, the upper and lower curves represent the range for the mean ± 1 SO. Plasma levels are corrected to 650 mg/68 kg. Lot numbers were not provided. The analytical procedure measured unchanged acetaminophen. This study was performed by McNeil.

Ty lenol elixi r

~~~ '~~ ~ -

1

1

0_

. SK-APAP e lixir

?P., '<~

5 4

co Q) 3 . <{

. -

'",~o- - o

01 7

0 -- 0

I

1

'o~

:=:-

~i:::. 0, ,.~

2

<-:-----:~o

8

I,Ie! .,

e~.

a. 9

o ... ~

8

-----~

co

Q) u

5

e - e McNe il tablet

Figure 5.

12

11

01

to each subject. Similar reductions in the range of the data were obtained in the remaining data sets (not shown) when weight corrections were made. Larger differences between individual plasma curves would have been expected if the subjects had not fasted. This monograph contains data submitted as of January 1, 1977.

'

-----

~'---"e

--

~

3

4

5

6

Time (hou rs)

Linear plots of plasma acetaminophen levels versus time following oral administration. Key: (a } 12 fasted subjects received 600 mg of acetaminophen as both SK-APAP (SKF) (solid curves) and Tylenol (McNeil) (dashed curves) elixirs; (b) 12 fasted $ubjects received 650 mg of acetaminophen as both SK-APAP (solid curves) and Tylenol (dashed curves) tablets. In each case, the upper and lower curves represent the mean ± 1 SO. Plasma levels are not corrected for weight. Lot numbers were not provided. The analytical procedure measured unchanged acetaminophen. This study was performed by Smith Kline and French.

Journal of the American Pharmaceutical Association

Monograph AuthorsC. Anthony Hunt, Assistant Professor of Pharmacy and Pharmaceutical Chemistry, School of Pharmacy, Univer~ity of California, San Francisco. Pamela R. Dunford, Staff Research Associate and PharmD candidate, School of Pharmacy, University of California, San Francisco.

References 1. An annotated list of drugs with a potential for therapeutic inequivalence based on current evidence of product bioavailability inequivalence, J. Am. Pharm. Assoc. NS13: 278-280, 1973. 2. Recommendation to HEW on mUlti-source drug list, J. Am. Pharm. Assoc. NS14: 556-557, 1974. 3. Mattok, G.L. , McGilveray, I.J., and Cook, D.: Can. J. Pharm. Sci. 6: 35, 1971. 4. S. Oie: "Plasma Protein Binding of Bilirubin and Its Pharmacokinetic Implications/ Pharmacokinetics of Acetam inophen in Anephric Patients," PhD thesis, State University of New York, Buffalo, New York (Sept.) 1975. 5. Cummings, A.J. , King, M.L. , and Martin, B.K.: Br. J. Pharmacol. Chemother. 29: 150, 1967. 6. Smith, G., and Mitchell, M.I. : Pharm. J. 188: 137 1962. 7. Sheth, B.B., Paruta, A.N ., and Ninger, F.C. : J. Pharm. Sci. 55: 1144, 1966. 8. Dittert, L.W., Caldwell, H.C., Adams, H.J., Irwin, G.M., andSwintosky, J.V.: J. Pharm. Sci. 57: 774, 1968.

Vol. NS 17, No.8, August 1977

Monograph CollaboratorsSalomon Stavchansky, PhD, College of Pharmacy, University of Texas, Austin, Texas. Christopher Rhodes, PhD, Department of Pharmacy, University of Rhode Island. Michael Winter, PhD, School of Pharmacy, University of California, San Francisco.

9. Martindale, the extra pharmacopoeia, 25th edition, The Pharmaceutical Press, London, England, 1967, p.40. 10. National formulary, 13th edition, Mack Publishing Co. , Easton, Pennsylvania, 1970, p. 856. 11 . Shane, N., and Kowblansky, M.: J. Pharm. Sci. 57: 1218, 1968. 12. Prescott, L.F., and Nimmo, J.: J. Mond. Pharm. 14: 253, 1971 . 13. Kalatzis, E.: J. Pharm. Sci. 59: 193, 1970. 14. Koshy, K.T., and Lach, J.L.: J. Pharm. Sci. 50: 113, 1961 . 15. Koshy, K.T. : Dis. Abstr. 21: 1387, 1960, University Microfilms, L.C. Card No. Mic 60-4385, Ann Arbor, Michigan. 16. Eide, G.J.: Acta Pharm. Suec. 10: 229, 1973. 17. Brodie, B.B., and Axelrod, J.: J. Pharmacol. Exp. Ther. 94: 22, 1948. 18. Prescott, L.F.: Clin. Pharmacol. Ther. 10: 383, 1970. 19. Welch, R.M., and Conney, A.H.: Clin. Chem. 11: 1064, 1965. 20. Prescott, L.F.: J. Pharm. Pharmacol. 23: 111, 1971 .

21 . Thomas, B.H., and Coldwell, B.B. : J. Pharm. Pharmacol. 24: 243, 1972. 22. Wong, L.T., Solomonraj, G., and Thomas, B.H.: J. Pharm. Sci. 65: 1064, 1976. 23. Duggin, G.G. : J. Chromatogr. 121: 156, 1976. 24. McGilveray, I.J., and Mattok, G.L. : J. Pharm. Pharmacol. 24: 615, 1972. 25. Albert, K.S., Sedman, A.J. , Wilkinson, P. , Stoll, R.G. , Murray, W.J., and Wagner, J.G.: J . Clin. Pharmacol. 14: 264, 1974. 26. Hedges, A. , Kaye, C.M., Maclay, W.P. , and Turner, P.: J. Clin. Pharmacol. 14: 363, 1974. 27. Shangraw, R.F., and Walkling, W.O.: J. Pharm. Sci. 60: 600, 1971. 28. Pagay, S.N., Poust, R.I. , and Colaizzi, J.L. : J. Pharm. Sci. 63: 44, 1974.

Published by American Pharmaceutical Association 2215 Constitution Ave ., NW Washington, DC 20037

521