Rheumatology and Rehabilitation, 1978, 17, 23
THE BIOAVAILABILITY OF BENORYLATE IN HOT BEVERAGES BY NICOLA A. BARRETT, M. E. PICKUP, J. R. LOWE, V. WRIGHT AND W. W. DOWNIE Clinical Pharmacology Unit, Royal Bath Hospital, Harrogate, and the Rheumatism Research Unit, University Department of Medicine, General Infirmary at Leeds
BENORYLATE (4-acetamidophenyl-2-acetoxybenzoate) is an anti-inflammatory analgesic and antipyretic drug used primarily in the treatment of rheumatoid arthritis and osteoarthrosis. It is an ester of acetylsahcylic acid and paracetamol but is not hydrolysed to these compounds until the drug has been absorbed from the gastro-intestinal tract thus rendering the drug less irritant to the gastric mucosa (Robertson, Glynn and Watson, 1972; Robertson, 1973). Benorylate is marketed as a suspension and, more recently, in a 750 mg tablet formulation. For some patients, continual administration of the suspension which is tasteless and possesses an unpalatable texture has proved tedious and it is recommended by the manufacturers that it may be taken with a beverage. Previous work by the manufacturers has shown that the suspension is stable in hot tea or coffee. However, no study has examined the effect of beverages in vivo. The present work investigated the relative bioavailability of benorylate (measured in terms of its salicylate content) given with water and with a hot beverage, coffee. MATERIALS AND METHODS Benorylate suspension (0.15 ml/kg) was administered orally to each of 20 normal healthy volunteers (9 female, 11 male, age 20-40 years) after an overnight fast. No food intake was allowed for four hours after drug administration. The suspension was given to each subject on two separate occasions at least one week apart, stirred either into 200 ml water or coffee. The allocation to the water or coffee group on the first occasion was determined by a random number technique. Timed urine collections In five subjects (4 male and 1 female), urine was collected half-hourly for the first 4 h, thence hourly up to 8 h and as produced up to 72 h. Urine production was boosted by drinking 100 ml water hourly up to 4 h. Urine volumes were recorded and 5 ml ahquots stored at —20 °C to await analysis. Bulk urine collections The remaining 15 subjects were each instructed to collect a bulk 72-h urine sample. The volume and pH were recorded and a 5 ml aliquot stored at —20 °C to await analysis. Accepted for publication June 1977. Requests for reprints to Dr. M. E. Pickup, Clinical Pharmacology Unit (Rheumatism Research), Royal Bath Hospital, Cornwall Road, Harrogate HG1 2PS. 23
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
SUMMARY It has been recommended that benorylate may be administered with hot beverages to overcome the problem of its relative unpalatability. Urine salicylate recovery used as a measure of bioavailability in 20 normal subjects has shown that hot coffee has no significant effect on drug availability from the orally administered suspension.
24
RHEUMATOLOGY AND REHABILITATION VOL. XVH NO. 1
Analytical procedure Urine samples (1 ml) were assayed for salicylate content by the method of Trinder (1954). Derivation of salicylate half-life from urine data
RESULTS Timed urine collections The cumulative recovery of salicylate (mean of five subjects) after benorylate with coflFee and with water is shown in Fig. 1. The results are expressed as a percentage of the calculated salicylate rather than aspirin content of the dose.
— £/_.,-water .- U ^ c o f f e e > o u a> at a c a> u
40
0
20
40
00
80
Time-hours
FIG. 1.—Cumulative urinary excretion data: total salicylate recovery plotted as a percentage of the original salicylate dose (mean±s.E.) excreted at a given time t hours (five subjects). • with water; A with coffee Salicylate elimination showed, in all but subject 5, zero-order kinetics initially followed by a first-order terminal exponential phase (Fig. 2), i.e. an initial phase where the elimination rate is constant (a plot of salicylate remaining to be excreted versus time is linear on standard graph paper but curved on a semi-logarithmic scale, Fig. 2), followed by a second phase where the elimination rate decreases with concentration (a plot of salicylate remaining versus time is linear on a semi-logarithmic scale). The change from zero- to first-order kinetics occurred approximately 10 hours after drug administration corresponding with a f/max— £/t (salicylate remaining to be excreted) value of 600-700 mg. Subject 5 showed first-order kinetics over the whole 72-h period.
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
Linear least-squares regression analysis was used to obtain the line of closest fit to the logarithms of the calculated values (Umax-Ui) at various times t of the terminal exponential phase, where Um^ is the maximum urinary salicylate recovery (mg) in a given subject and Ut the cumulative recovery at time t. The sigma-minus method for drug half-lives was described by Gibaldi and Perrier (1975a).
BARRETT ETAL.: BENORYLATE IN HOT BEVERAGES
25
2000 •
.
10
20
30
40
SO
10
70
80
Tlma-hourt.
Fio. 2.—Salicylate elimination in subject 2 after benoral administration with water (A) and coffee ( • ) . Half-lives derived from the terminal first-order elimination phases ranged from 8.2 to 18.9 h (Table). Bulked urine collections Salicylate recovery after 72 h in all 20 subjects is presented in the Table together with the total urine volume in that time and the mean urine pH. The mean percentage recovered was 60.3 (range 28.1-79.7%) after benorylate given with water and 57.1 (range 37.6-78.1%) after administration with coffee. The Student's t test for paired values indicated no significant difference in the individual recoveries after dosing with water and coffee. DISCUSSION Drug bioavailability may be estimated using the area under the plasma concentration versus time plot, steady state plasma level after multiple dosing, or urinary excretion data (Gibaldi and Perrier, 1975*). Because of the relatively slow absorption of benorylate (Liss and Palme, 1969) which would necessitate blood sampling over a long period and the very low plasma salicylate levels expected following single doses, the urinary excretion method was used. It was shown (Fig. 1) that approximately 95 % of the total salicylate excreted (Umax) is recovered within 72 h. A reliable estimate of bioavailability of salicylate
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
0
Approxlmete change from zero to flrtt-ordor kinetic*
26
RHEUMATOLOGY AND REHABILITATION VOL. XVII NO. 1
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
a o&
S1
cd M I
j i-i t s f-i cs rs T-i tN i-i
OO
o
o o
•o OO
o o
.76
.07
.53
.51
.42
.85
.)4
.53
.53
.16
s
.62
.53 o
O
.98
»
.53
-
.89
O
r v o v i 5 ' n Q * n o o o o > r i v a y 5 i t « --i n cs ri ^f i-n-i i-i ^-r-wnn
t s t s cs i-«
.17
C
CM
o 00
a
o as
o
m oo
OS 00
• ^ • v - i \ c c - o o o \ o - - ( S r - ,
ON
v-t
00
00
00
i t v i \ c r ^ o o o o
-H
BARRETT ET AL.: BENORYLATE IN HOT BEVERAGES
27
ACKNOWLEDGMENTS
We wish to thank Winthrop Laboratories for financial support for this work. The Clinical Pharmacology Unit acknowledges the support of Roche Products Ltd.
REFERENCES
G. D., DAY, R. O., GRAHAM, G. G. and PAULL, P. D. (1975) "Salicylates in Rheumatoid Arthritis". Clin. Rheum. Dis. 1, 245-65. GIBALDI, M. and PERREER, D. (1975a) Pharmacokinetics ed.: J. Swarbrick. New York: Marcel Dekker. pp 8-11, 42. (19756) Pharmacokinetics ed.: J. Swarbrick. New York: Marcel Dekker. p. 164. LEVY, G. (1961) "Comparison of Dissolution and Absorption Rates of Different Commercial Aspirin Tablets". /. Pharm. Sci. 50, 388-92. (1965) "Pharmacokinetics of Salicylate Elimination in Man". /. Pharm. Sci. 54, 959-67. and LEONARDS, J. R. (1971) "Urine pH and Salicylate Therapy". /. Am. Med. Assoc. Ill, 81. LBS, E. and PALME, G. (1969) "The Pharmacokinetic Behaviour of the New Acetylsalicylic Derivative 4-Acetamidophenyl-2-acetoxybenzoate in Animal Tests". Arzneimittelforsch. 19, 1177-80. CHAMPION,
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
from benorylate can therefore be obtained from the 72-h salicylate recovery measured in the 20 subjects. The absence of a significant intra-subject difference in these figures following water and coffee co-administration indicated that drinking benorylate in coffee did not alter drug availability significantly when compared with water. The analytical method used for salicylate was sensitive to two of the four major salicylate metabolites reported, i.e. salicylic acid and salicyluric acid (Levy, 1961). In a single-dose study, Robertson et al. (1972) found that total salicylic acid metabolites recovered amounted to 93 % of the dose, the recovery of salicylic acid and salicyluric acid amounting to 49 % of dose. The latter figure is in approximate agreement with those obtained in the present study (Table). Salicylate elimination showed zero-order kinetics during the initial phase of study (up to 10 b approximately). The observed change from zero- to first-order kinetics was comparable with data obtained by Levy (1965). It can be assumed that zero-order kinetics occurred due to the ingestion of a sufficiently large dose of benorylate to produce plasma salicylate in concentrations high enough to saturate liver enzymes responsible for salicylate metabolism (Paulus et al., 1971). The one salicylate metabolite (salicyluric acid) measured in addition to free salicylate is itself formed by a limited-capacity enzyme system. Salicylate elimination is highly dependent on urine volume and pH (Levy and Leonards, 1971; Champion et al., 1975). Any increase in salicylate half-life is normally due to a small urine output or low urine pH. The increase in salicylate half-life demonstrated within each individual (Table) appears to be due to a lower urine output rather than a more acidic urine. Neither urine production nor pH, however, significantly affected the percentage recovery of salicylate since no correlation could be demonstrated between these variables. Bioavailability studies have shown an equivalent production of salicylate in the urine whether benorylate is given in water or in hot coffee. These results suggest that equivalent body levels of salicylate are produced and therefore pharmacological activity is not impaired by co-administration of benorylate with hot coffee.
28
RHEUMATOLOGY A N D REHABILITATION VOL. XVH NO. 1
PAULUS, H. E., SIEQEL, M., MONOAN, E., OKUN, R. and CALABRO, J. J. (1971) "Variations of
Serum Concentrations and Half-life of Salicylate in Patients with Rheumatoid Arthritis". Arthritis Rheum. 14, 527-32. ROBERTSON, A., GLYNN, J. P. and WATSON, A. K. (1972) "The Absorption and Metabolism in
Man of 4-Acetamidophenyl-2-acetoxybenzoate". Xenobiotica 2, 339-47. (1973) "Benorylate—The Rationale". In: A Symposium on Betwrylate. Rheumatol. Rehabil. Suppl. pp. 7-16. TRINDER, P. (1954) "Rapid Determination of Salicylate in Biological Fluids". Biochem. J. 57, 301-3.
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
THE BIOAVAILABILITY OF BENORYLATE IN HOT BEVERAGES BY NICOLA A. BARRETT, M. E. PICKUP, J. R. LOWE, V. WRIGHT AND W. W. DOWNIE Clinical Pharmacology Unit, Royal Bath Hospital, Harrogate, and the Rheumatism Research Unit, University Department of Medicine, General Infirmary at Leeds
BENORYLATE (4-acetamidophenyl-2-acetoxybenzoate) is an anti-inflammatory analgesic and antipyretic drug used primarily in the treatment of rheumatoid arthritis and osteoarthrosis. It is an ester of acetylsahcylic acid and paracetamol but is not hydrolysed to these compounds until the drug has been absorbed from the gastro-intestinal tract thus rendering the drug less irritant to the gastric mucosa (Robertson, Glynn and Watson, 1972; Robertson, 1973). Benorylate is marketed as a suspension and, more recently, in a 750 mg tablet formulation. For some patients, continual administration of the suspension which is tasteless and possesses an unpalatable texture has proved tedious and it is recommended by the manufacturers that it may be taken with a beverage. Previous work by the manufacturers has shown that the suspension is stable in hot tea or coffee. However, no study has examined the effect of beverages in vivo. The present work investigated the relative bioavailability of benorylate (measured in terms of its salicylate content) given with water and with a hot beverage, coffee. MATERIALS AND METHODS Benorylate suspension (0.15 ml/kg) was administered orally to each of 20 normal healthy volunteers (9 female, 11 male, age 20-40 years) after an overnight fast. No food intake was allowed for four hours after drug administration. The suspension was given to each subject on two separate occasions at least one week apart, stirred either into 200 ml water or coffee. The allocation to the water or coffee group on the first occasion was determined by a random number technique. Timed urine collections In five subjects (4 male and 1 female), urine was collected half-hourly for the first 4 h, thence hourly up to 8 h and as produced up to 72 h. Urine production was boosted by drinking 100 ml water hourly up to 4 h. Urine volumes were recorded and 5 ml ahquots stored at —20 °C to await analysis. Bulk urine collections The remaining 15 subjects were each instructed to collect a bulk 72-h urine sample. The volume and pH were recorded and a 5 ml aliquot stored at —20 °C to await analysis. Accepted for publication June 1977. Requests for reprints to Dr. M. E. Pickup, Clinical Pharmacology Unit (Rheumatism Research), Royal Bath Hospital, Cornwall Road, Harrogate HG1 2PS. 23
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
SUMMARY It has been recommended that benorylate may be administered with hot beverages to overcome the problem of its relative unpalatability. Urine salicylate recovery used as a measure of bioavailability in 20 normal subjects has shown that hot coffee has no significant effect on drug availability from the orally administered suspension.
24
RHEUMATOLOGY AND REHABILITATION VOL. XVH NO. 1
Analytical procedure Urine samples (1 ml) were assayed for salicylate content by the method of Trinder (1954). Derivation of salicylate half-life from urine data
RESULTS Timed urine collections The cumulative recovery of salicylate (mean of five subjects) after benorylate with coflFee and with water is shown in Fig. 1. The results are expressed as a percentage of the calculated salicylate rather than aspirin content of the dose.
— £/_.,-water .- U ^ c o f f e e > o u a> at a c a> u
40
0
20
40
00
80
Time-hours
FIG. 1.—Cumulative urinary excretion data: total salicylate recovery plotted as a percentage of the original salicylate dose (mean±s.E.) excreted at a given time t hours (five subjects). • with water; A with coffee Salicylate elimination showed, in all but subject 5, zero-order kinetics initially followed by a first-order terminal exponential phase (Fig. 2), i.e. an initial phase where the elimination rate is constant (a plot of salicylate remaining to be excreted versus time is linear on standard graph paper but curved on a semi-logarithmic scale, Fig. 2), followed by a second phase where the elimination rate decreases with concentration (a plot of salicylate remaining versus time is linear on a semi-logarithmic scale). The change from zero- to first-order kinetics occurred approximately 10 hours after drug administration corresponding with a f/max— £/t (salicylate remaining to be excreted) value of 600-700 mg. Subject 5 showed first-order kinetics over the whole 72-h period.
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
Linear least-squares regression analysis was used to obtain the line of closest fit to the logarithms of the calculated values (Umax-Ui) at various times t of the terminal exponential phase, where Um^ is the maximum urinary salicylate recovery (mg) in a given subject and Ut the cumulative recovery at time t. The sigma-minus method for drug half-lives was described by Gibaldi and Perrier (1975a).
BARRETT ETAL.: BENORYLATE IN HOT BEVERAGES
25
2000 •
.
10
20
30
40
SO
10
70
80
Tlma-hourt.
Fio. 2.—Salicylate elimination in subject 2 after benoral administration with water (A) and coffee ( • ) . Half-lives derived from the terminal first-order elimination phases ranged from 8.2 to 18.9 h (Table). Bulked urine collections Salicylate recovery after 72 h in all 20 subjects is presented in the Table together with the total urine volume in that time and the mean urine pH. The mean percentage recovered was 60.3 (range 28.1-79.7%) after benorylate given with water and 57.1 (range 37.6-78.1%) after administration with coffee. The Student's t test for paired values indicated no significant difference in the individual recoveries after dosing with water and coffee. DISCUSSION Drug bioavailability may be estimated using the area under the plasma concentration versus time plot, steady state plasma level after multiple dosing, or urinary excretion data (Gibaldi and Perrier, 1975*). Because of the relatively slow absorption of benorylate (Liss and Palme, 1969) which would necessitate blood sampling over a long period and the very low plasma salicylate levels expected following single doses, the urinary excretion method was used. It was shown (Fig. 1) that approximately 95 % of the total salicylate excreted (Umax) is recovered within 72 h. A reliable estimate of bioavailability of salicylate
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
0
Approxlmete change from zero to flrtt-ordor kinetic*
26
RHEUMATOLOGY AND REHABILITATION VOL. XVII NO. 1
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
a o&
S1
cd M I
j i-i t s f-i cs rs T-i tN i-i
OO
o
o o
•o OO
o o
.76
.07
.53
.51
.42
.85
.)4
.53
.53
.16
s
.62
.53 o
O
.98
»
.53
-
.89
O
r v o v i 5 ' n Q * n o o o o > r i v a y 5 i t « --i n cs ri ^f i-n-i i-i ^-r-wnn
t s t s cs i-«
.17
C
CM
o 00
a
o as
o
m oo
OS 00
• ^ • v - i \ c c - o o o \ o - - ( S r - ,
ON
v-t
00
00
00
i t v i \ c r ^ o o o o
-H
BARRETT ET AL.: BENORYLATE IN HOT BEVERAGES
27
ACKNOWLEDGMENTS
We wish to thank Winthrop Laboratories for financial support for this work. The Clinical Pharmacology Unit acknowledges the support of Roche Products Ltd.
REFERENCES
G. D., DAY, R. O., GRAHAM, G. G. and PAULL, P. D. (1975) "Salicylates in Rheumatoid Arthritis". Clin. Rheum. Dis. 1, 245-65. GIBALDI, M. and PERREER, D. (1975a) Pharmacokinetics ed.: J. Swarbrick. New York: Marcel Dekker. pp 8-11, 42. (19756) Pharmacokinetics ed.: J. Swarbrick. New York: Marcel Dekker. p. 164. LEVY, G. (1961) "Comparison of Dissolution and Absorption Rates of Different Commercial Aspirin Tablets". /. Pharm. Sci. 50, 388-92. (1965) "Pharmacokinetics of Salicylate Elimination in Man". /. Pharm. Sci. 54, 959-67. and LEONARDS, J. R. (1971) "Urine pH and Salicylate Therapy". /. Am. Med. Assoc. Ill, 81. LBS, E. and PALME, G. (1969) "The Pharmacokinetic Behaviour of the New Acetylsalicylic Derivative 4-Acetamidophenyl-2-acetoxybenzoate in Animal Tests". Arzneimittelforsch. 19, 1177-80. CHAMPION,
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
from benorylate can therefore be obtained from the 72-h salicylate recovery measured in the 20 subjects. The absence of a significant intra-subject difference in these figures following water and coffee co-administration indicated that drinking benorylate in coffee did not alter drug availability significantly when compared with water. The analytical method used for salicylate was sensitive to two of the four major salicylate metabolites reported, i.e. salicylic acid and salicyluric acid (Levy, 1961). In a single-dose study, Robertson et al. (1972) found that total salicylic acid metabolites recovered amounted to 93 % of the dose, the recovery of salicylic acid and salicyluric acid amounting to 49 % of dose. The latter figure is in approximate agreement with those obtained in the present study (Table). Salicylate elimination showed zero-order kinetics during the initial phase of study (up to 10 b approximately). The observed change from zero- to first-order kinetics was comparable with data obtained by Levy (1965). It can be assumed that zero-order kinetics occurred due to the ingestion of a sufficiently large dose of benorylate to produce plasma salicylate in concentrations high enough to saturate liver enzymes responsible for salicylate metabolism (Paulus et al., 1971). The one salicylate metabolite (salicyluric acid) measured in addition to free salicylate is itself formed by a limited-capacity enzyme system. Salicylate elimination is highly dependent on urine volume and pH (Levy and Leonards, 1971; Champion et al., 1975). Any increase in salicylate half-life is normally due to a small urine output or low urine pH. The increase in salicylate half-life demonstrated within each individual (Table) appears to be due to a lower urine output rather than a more acidic urine. Neither urine production nor pH, however, significantly affected the percentage recovery of salicylate since no correlation could be demonstrated between these variables. Bioavailability studies have shown an equivalent production of salicylate in the urine whether benorylate is given in water or in hot coffee. These results suggest that equivalent body levels of salicylate are produced and therefore pharmacological activity is not impaired by co-administration of benorylate with hot coffee.
28
RHEUMATOLOGY A N D REHABILITATION VOL. XVH NO. 1
PAULUS, H. E., SIEQEL, M., MONOAN, E., OKUN, R. and CALABRO, J. J. (1971) "Variations of
Serum Concentrations and Half-life of Salicylate in Patients with Rheumatoid Arthritis". Arthritis Rheum. 14, 527-32. ROBERTSON, A., GLYNN, J. P. and WATSON, A. K. (1972) "The Absorption and Metabolism in
Man of 4-Acetamidophenyl-2-acetoxybenzoate". Xenobiotica 2, 339-47. (1973) "Benorylate—The Rationale". In: A Symposium on Betwrylate. Rheumatol. Rehabil. Suppl. pp. 7-16. TRINDER, P. (1954) "Rapid Determination of Salicylate in Biological Fluids". Biochem. J. 57, 301-3.
Downloaded from http://rheumatology.oxfordjournals.org/ at Michigan State University on June 9, 2015
