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Concentration of propoxyphene in human plasma following repeated oral doses
TOXICOuHiY
AND APPLIED PHARMACOLQGY
Concentration
19,493-497(1971)
of Propoxyphene Following Repeated
in Human Oral Doses
Plasma
ROBERTL. WOLEN, CHARLES M. GRUBER, JR., GLENN F. KIPLINGER, AND NORMAN E. SCHOLZ Lilly Laboratory for Clinical Research, Marion County General Hospital, and Eli Lilly and Company, Indianapolis, Indiana 46206 Received January 7, 1970
Concentration of Propoxyphenein Human PlasmaFollowing Repeated Oral Doses,WOLEN, ROBERT L., GRUBER, CHARLES M., JR., KIPLINGER, GLENN F., and SCHOLZ, NORMAN E. (1971).Toxicol. Appl. Pharmacol. 19, 493-497. Propoxyphene hydrochloride was administeredpo to normal human volunteers. Included in the crossoverstudy were po dosesof propoxyphenenapsylateequimolar with the dosesof the hydrochloride salt. The concentrationsof propoxyphene in the plasmaof thesesubjectswere determinedperiodically after each medication. The differencesin plasma concentrationsfollowing thesesaltswere small in comparisonwith those among subjectsand amongdoses.It was,therefore, concludedthat these differenceshad little, if any, therapeutic importance. Two salts of propoxyphene, the hydrochloride’ and the napsylate,2 have been used as analgesicmedications. Careful comparisons of the concentrations of propoxyphene in the plasma of human subjects following the administration of these compounds were not possible prior to the development of a sensitive method of determination (Wolen and Gruber, 1968). This report presents time-related curves following equimolar, graded, oral dosesof these salts. METHODS The analytical method (Wolen and Gruber, 1968)for propoxyphene assayis basedon solvent extraction of the drug from plasmaat neutral or near neutral pH values followed by purification and concentration of the extract. The concentrated extract is then analyzed by gas chromatography using a short column with a liquid phase of silicone gum rubber. Quantitation is achieved by the addition of d-pyrroliphene hydrochloride, as a massinternal standard, to the sampleprior to extraction. The ratio of peak heights of propoxyphene to pyrroliphene on the chromatogram is compared with the ratios derived from standard prepared in plasma and treated in the same manner as the sample. Four normal, adult, male volunteers participated in the study (Table 1). They were admitted to a special research ward at the Indiana State Reformatory for the duration of the study. They were instructed to fast for at least 8 hr prior to the administration of the 1st and 13th dosesof each medication. Crossover of medications was usedwith an ’ Propoxyphene hydrochlorideisavailableasDarvon@, a productof Eli Lilly andCompany. 2 Propoxyphene napsylate hasthetrademarkDoloxene@, a productof Eli Lilly andCompany. 493
494
ET AL.
WOLEN
interval of 4 days between each series of doses. Each series included 13 doses administered at 6-hr intervals. TABLE 1 PHYSICAL
CHARACTERISTICS OF THE PARTICIPANTS IN THIS STUDY
Subjecta
Weight
Age
1
176 174 152 163
30 27 28 29
2 3 4
’ All subjectswere white males. Blood specimensfor analysis were obtained just before the Ist, 5th, 9th, and 13th doseswere administered and on the 4th, 5th, and 6th hr after the 1st dose, and on the 4th, 5th, 6th, and 8th hr after the 13th dose of each medication. The medications were single capsules,identical in appearance. The 4 serieswere 32 and 65 mg of propoxyphene hydrochloride and 50 and 100mg of propoxyphene napsylate. The order of administration was based on a Latin square. RESULTS From Table 2, the differences in the magnitude of the responsesamong thesesubjects are apparent. However, the plasma concentrations within each subject are fairly consistent. The differences among the subjects are not time related; therefore, the mean TABLE 2 CONCENTRATION OF PROPOXYPHENE DURING THE SERIES OF 13 DOSES OF
IN THE PLASMA
4 MEDICATIONS
OF HUMANS AT INTERVALS REPORTED CHRONOLOGICALLY
Plasmaconcentration @g/i) Hr after 1st dose Medication 32 mg HCl”
Subject
0
1
0
2 3 4 65 mg HCI
1 2 3 4
50 mg Napb
1 2 3 4
100mg Nap
I 2 3 4
4
5
6
24
48
19 29 25
43 25 42
73 43 73
72
80 7 22 19 21 50 9 47 41 39 167 11 61 41 34 64 81 77 8 57 53 41 72 117 125 2 48 36 23 62 86 134 2 97 76 66 115 233 218 6 114 66 47 108 197 53’ 15 50 34 33 48 59 74 17 35 26 28 44 55 54 2 37 25 24 45 71 73 8 65 49 61 87 81 8 67 72 50 102 122 114 3 30 24 19 56 72 101 4 54 38 34 171 202 182 5 103 78 62 191 233 234
aHydrochloridesalt of propoxyphene c May representmisseddose.
76
77
78
80
129 74 99 149 211 162 210 259 96 55 60 205 162
85 54
92 45 83 102 182 106 150 189 70 47 99 106 106
109 39 63 71 66 94 137 137 58 48 74 85 96
142 195 153 208 228 84 50 122 221 123
135 116 260 259
212 204
98 174 175
’ Napsylatesaltof propoxyphene.
75 155 188
PROPOXYPHENEIN
495
HUMAN PLASMA
values presented in Figs. 1 and 2 are representative of the family of curves associated with each medication. The responses to the 2 doses of propoxyphene are distinctive, but the responses to equimolar doses of the 2 salts are not. ,,.?. Nap., I’m““J ,... ~,” ,_.” “‘2 (..” ;’ /
..,_,,~ ’
’
-4 HCI.65/>I”
FIG. 1. Mean concentrations of propoxyphene in the plasma of humans 6 hr after the specified doses. Medication was given every 6 hr.
Hour
FIG. 2. Mean concentrations of propoxyphene 1st and 13th doses of each medication.
of Experfment
in the plasma of humans at intervals following
the
Several positive rather than negative slopes were observed in the biologic half-life determinations. The concentration of propoxyphene in the plasma was estimated for each subject on the 5th hr following the 1st and 13th doses of each series of medications. The logarithmic least squares method was employed in these estimations. These values
496
WOLEN
ET AL.
are presented in Table 3 and the variance analysis in Table 4. In this analysis the treatment effects are separated into 7 orthogonal contrasts, each with 1 degree of freedom. The 1st contrast, dose number, demonstrates a significant increase in the concentration 3
TABLE ESTIMATED
HUMAN
PLASMA CONCENTRATIONS AT THE ~TH HOUR ORAL ADMINISTRATION OF PROPOXYPHENE
Hydrochloride 32 mg 1
13
1
1 2 3 4
24” 21 42 44
104 58 90 129
50 34 79 71
* Plasma concentration
Napsylate 50 mg
65 mg
Subject
Dose number 13 1 186 140 189 223
ANALYSIS
38 29 28 57
13
1
13
83 51 85 172
62 24 41 79
131 115 216 216
4
OF THE ESTIMATED PLASMA CONCENTRATIONS AFTER DOSES OF PROPOXVPHENE
Sumof
Degreesof
Mean
Sourceof variance
squares
freedom
square
Subjects Treatments Dose number Dose, mg Number x mg Salt Salt x number Salt x mg Salt x number x mg Subject x treatment
17,371
Total
1OOmg
expressed as pg/l. TABLE
VARIANCE
FOLLOWING
3
95,147
9,551 122,069
(:, (1) (1) (1) (1) (1) (1) 21
5,790 13,592 67,070 20,050 7,411 102 57 442 15 459
AT THE ~TH HOUR
F value 12.61 29.61 146.12 43.68 16.14
PC
0.001 0.001 0.001 0.001 0.001
31
of propoxyphene in the plasma following the 13th dose as compared with the 1st. The sameis true with the 2nd contrast, dosemg, which compares the 65-100 mg dose with the 32-50 mg dose. Contrast 3 indicates that the responseover time to the larger doseof propoxyphene was greater than the responseover time to the smaller dose. All of the contrasts (4, $6, and 7) which are related to the saltsof propoxyphene failed to demonstrate any significant effects indicating the similarity in the responsesto these salts. A similar analysiswas made with the data obtained on the 8th hr after the last dose of each medication. This analysis also demonstrates differences between the doses, but not between the salts.
PROPOXYPHENE
IN HUMAN
PLASMA
497
The accumulation of propoxyphene following repeated doses of the 2 salts is illustrated in Fig. 1. It appears that by the time the 9th dose was given (48 hr), a relatively steady state was achieved. The fluctuation in this steady state is indicated by the curves (the 76th to 80th hr) in Fig. 2. The plasma concentration decreased similarly in both post medication periods. The average decrease with the higher doses was just less than 50 ‘A in 4 hr; therefore, an average biologic half-life of slightly more than 4 hr after oral doses is indicated. DISCUSSION The results obtained with repeated doses of propoxyphene were not unexpected. Similar results have been reported (Hammer and Brodie, 1967; Hammer et al., 1967). A significant increase in the concentration of propoxyphene in the plasma occurred when subjects were administered repeated doses at 6-hr intervals for 13 doses. As the number of doses increased, the plasma response decreased; by the time the 9th dose was given, the concentration of propoxyphene in the plasma was essentially the same as it was 4 doses later. Thus, a plateau effect is seen by the end of the 2nd day. The concentration of propoxyphene in the plasma also has a direct relationship with the dose administered. The plateau effect occurs at a higher concentration when larger doses of propoxyphene are administered; however, the time of occurrence appears to be essentially unchanged. ACKNOWLEDGMENTS We wish to thank Mr. TomCollins, theinmates, and the staff of the Indiana State Reformatory at Pendleton for the parts they played in this research project. REFERENCES W., and BRODIE, B. B. (1967). Application of isotope derivative technique to assay of secondary amines: Estimation of desipramine by acetylation with H3-acetic anhydride. J. Pharmacol. Exp. Ther. 157, 503-508. HAMMER, W., IDESTROM, C. M., and SJOQVIST, F. (1967).Chemicalcontrol of antidepressant drug therapy. Proc. Znt. Symp. Antidepressant Drugs, Ist, Milan, 1966, pp. 301-310. WOLEN, R. L., and GRUBER, C. M., JR. (1968).Determination of propoxyphene in human plasmaby gaschromatography.Anal. Chem. 40, 1243-1246. HAMMER,
AND APPLIED PHARMACOLQGY
Concentration
19,493-497(1971)
of Propoxyphene Following Repeated
in Human Oral Doses
Plasma
ROBERTL. WOLEN, CHARLES M. GRUBER, JR., GLENN F. KIPLINGER, AND NORMAN E. SCHOLZ Lilly Laboratory for Clinical Research, Marion County General Hospital, and Eli Lilly and Company, Indianapolis, Indiana 46206 Received January 7, 1970
Concentration of Propoxyphenein Human PlasmaFollowing Repeated Oral Doses,WOLEN, ROBERT L., GRUBER, CHARLES M., JR., KIPLINGER, GLENN F., and SCHOLZ, NORMAN E. (1971).Toxicol. Appl. Pharmacol. 19, 493-497. Propoxyphene hydrochloride was administeredpo to normal human volunteers. Included in the crossoverstudy were po dosesof propoxyphenenapsylateequimolar with the dosesof the hydrochloride salt. The concentrationsof propoxyphene in the plasmaof thesesubjectswere determinedperiodically after each medication. The differencesin plasma concentrationsfollowing thesesaltswere small in comparisonwith those among subjectsand amongdoses.It was,therefore, concludedthat these differenceshad little, if any, therapeutic importance. Two salts of propoxyphene, the hydrochloride’ and the napsylate,2 have been used as analgesicmedications. Careful comparisons of the concentrations of propoxyphene in the plasma of human subjects following the administration of these compounds were not possible prior to the development of a sensitive method of determination (Wolen and Gruber, 1968). This report presents time-related curves following equimolar, graded, oral dosesof these salts. METHODS The analytical method (Wolen and Gruber, 1968)for propoxyphene assayis basedon solvent extraction of the drug from plasmaat neutral or near neutral pH values followed by purification and concentration of the extract. The concentrated extract is then analyzed by gas chromatography using a short column with a liquid phase of silicone gum rubber. Quantitation is achieved by the addition of d-pyrroliphene hydrochloride, as a massinternal standard, to the sampleprior to extraction. The ratio of peak heights of propoxyphene to pyrroliphene on the chromatogram is compared with the ratios derived from standard prepared in plasma and treated in the same manner as the sample. Four normal, adult, male volunteers participated in the study (Table 1). They were admitted to a special research ward at the Indiana State Reformatory for the duration of the study. They were instructed to fast for at least 8 hr prior to the administration of the 1st and 13th dosesof each medication. Crossover of medications was usedwith an ’ Propoxyphene hydrochlorideisavailableasDarvon@, a productof Eli Lilly andCompany. 2 Propoxyphene napsylate hasthetrademarkDoloxene@, a productof Eli Lilly andCompany. 493
494
ET AL.
WOLEN
interval of 4 days between each series of doses. Each series included 13 doses administered at 6-hr intervals. TABLE 1 PHYSICAL
CHARACTERISTICS OF THE PARTICIPANTS IN THIS STUDY
Subjecta
Weight
Age
1
176 174 152 163
30 27 28 29
2 3 4
’ All subjectswere white males. Blood specimensfor analysis were obtained just before the Ist, 5th, 9th, and 13th doseswere administered and on the 4th, 5th, and 6th hr after the 1st dose, and on the 4th, 5th, 6th, and 8th hr after the 13th dose of each medication. The medications were single capsules,identical in appearance. The 4 serieswere 32 and 65 mg of propoxyphene hydrochloride and 50 and 100mg of propoxyphene napsylate. The order of administration was based on a Latin square. RESULTS From Table 2, the differences in the magnitude of the responsesamong thesesubjects are apparent. However, the plasma concentrations within each subject are fairly consistent. The differences among the subjects are not time related; therefore, the mean TABLE 2 CONCENTRATION OF PROPOXYPHENE DURING THE SERIES OF 13 DOSES OF
IN THE PLASMA
4 MEDICATIONS
OF HUMANS AT INTERVALS REPORTED CHRONOLOGICALLY
Plasmaconcentration @g/i) Hr after 1st dose Medication 32 mg HCl”
Subject
0
1
0
2 3 4 65 mg HCI
1 2 3 4
50 mg Napb
1 2 3 4
100mg Nap
I 2 3 4
4
5
6
24
48
19 29 25
43 25 42
73 43 73
72
80 7 22 19 21 50 9 47 41 39 167 11 61 41 34 64 81 77 8 57 53 41 72 117 125 2 48 36 23 62 86 134 2 97 76 66 115 233 218 6 114 66 47 108 197 53’ 15 50 34 33 48 59 74 17 35 26 28 44 55 54 2 37 25 24 45 71 73 8 65 49 61 87 81 8 67 72 50 102 122 114 3 30 24 19 56 72 101 4 54 38 34 171 202 182 5 103 78 62 191 233 234
aHydrochloridesalt of propoxyphene c May representmisseddose.
76
77
78
80
129 74 99 149 211 162 210 259 96 55 60 205 162
85 54
92 45 83 102 182 106 150 189 70 47 99 106 106
109 39 63 71 66 94 137 137 58 48 74 85 96
142 195 153 208 228 84 50 122 221 123
135 116 260 259
212 204
98 174 175
’ Napsylatesaltof propoxyphene.
75 155 188
PROPOXYPHENEIN
495
HUMAN PLASMA
values presented in Figs. 1 and 2 are representative of the family of curves associated with each medication. The responses to the 2 doses of propoxyphene are distinctive, but the responses to equimolar doses of the 2 salts are not. ,,.?. Nap., I’m““J ,... ~,” ,_.” “‘2 (..” ;’ /
..,_,,~ ’
’
-4 HCI.65/>I”
FIG. 1. Mean concentrations of propoxyphene in the plasma of humans 6 hr after the specified doses. Medication was given every 6 hr.
Hour
FIG. 2. Mean concentrations of propoxyphene 1st and 13th doses of each medication.
of Experfment
in the plasma of humans at intervals following
the
Several positive rather than negative slopes were observed in the biologic half-life determinations. The concentration of propoxyphene in the plasma was estimated for each subject on the 5th hr following the 1st and 13th doses of each series of medications. The logarithmic least squares method was employed in these estimations. These values
496
WOLEN
ET AL.
are presented in Table 3 and the variance analysis in Table 4. In this analysis the treatment effects are separated into 7 orthogonal contrasts, each with 1 degree of freedom. The 1st contrast, dose number, demonstrates a significant increase in the concentration 3
TABLE ESTIMATED
HUMAN
PLASMA CONCENTRATIONS AT THE ~TH HOUR ORAL ADMINISTRATION OF PROPOXYPHENE
Hydrochloride 32 mg 1
13
1
1 2 3 4
24” 21 42 44
104 58 90 129
50 34 79 71
* Plasma concentration
Napsylate 50 mg
65 mg
Subject
Dose number 13 1 186 140 189 223
ANALYSIS
38 29 28 57
13
1
13
83 51 85 172
62 24 41 79
131 115 216 216
4
OF THE ESTIMATED PLASMA CONCENTRATIONS AFTER DOSES OF PROPOXVPHENE
Sumof
Degreesof
Mean
Sourceof variance
squares
freedom
square
Subjects Treatments Dose number Dose, mg Number x mg Salt Salt x number Salt x mg Salt x number x mg Subject x treatment
17,371
Total
1OOmg
expressed as pg/l. TABLE
VARIANCE
FOLLOWING
3
95,147
9,551 122,069
(:, (1) (1) (1) (1) (1) (1) 21
5,790 13,592 67,070 20,050 7,411 102 57 442 15 459
AT THE ~TH HOUR
F value 12.61 29.61 146.12 43.68 16.14
PC
0.001 0.001 0.001 0.001 0.001
31
of propoxyphene in the plasma following the 13th dose as compared with the 1st. The sameis true with the 2nd contrast, dosemg, which compares the 65-100 mg dose with the 32-50 mg dose. Contrast 3 indicates that the responseover time to the larger doseof propoxyphene was greater than the responseover time to the smaller dose. All of the contrasts (4, $6, and 7) which are related to the saltsof propoxyphene failed to demonstrate any significant effects indicating the similarity in the responsesto these salts. A similar analysiswas made with the data obtained on the 8th hr after the last dose of each medication. This analysis also demonstrates differences between the doses, but not between the salts.
PROPOXYPHENE
IN HUMAN
PLASMA
497
The accumulation of propoxyphene following repeated doses of the 2 salts is illustrated in Fig. 1. It appears that by the time the 9th dose was given (48 hr), a relatively steady state was achieved. The fluctuation in this steady state is indicated by the curves (the 76th to 80th hr) in Fig. 2. The plasma concentration decreased similarly in both post medication periods. The average decrease with the higher doses was just less than 50 ‘A in 4 hr; therefore, an average biologic half-life of slightly more than 4 hr after oral doses is indicated. DISCUSSION The results obtained with repeated doses of propoxyphene were not unexpected. Similar results have been reported (Hammer and Brodie, 1967; Hammer et al., 1967). A significant increase in the concentration of propoxyphene in the plasma occurred when subjects were administered repeated doses at 6-hr intervals for 13 doses. As the number of doses increased, the plasma response decreased; by the time the 9th dose was given, the concentration of propoxyphene in the plasma was essentially the same as it was 4 doses later. Thus, a plateau effect is seen by the end of the 2nd day. The concentration of propoxyphene in the plasma also has a direct relationship with the dose administered. The plateau effect occurs at a higher concentration when larger doses of propoxyphene are administered; however, the time of occurrence appears to be essentially unchanged. ACKNOWLEDGMENTS We wish to thank Mr. TomCollins, theinmates, and the staff of the Indiana State Reformatory at Pendleton for the parts they played in this research project. REFERENCES W., and BRODIE, B. B. (1967). Application of isotope derivative technique to assay of secondary amines: Estimation of desipramine by acetylation with H3-acetic anhydride. J. Pharmacol. Exp. Ther. 157, 503-508. HAMMER, W., IDESTROM, C. M., and SJOQVIST, F. (1967).Chemicalcontrol of antidepressant drug therapy. Proc. Znt. Symp. Antidepressant Drugs, Ist, Milan, 1966, pp. 301-310. WOLEN, R. L., and GRUBER, C. M., JR. (1968).Determination of propoxyphene in human plasmaby gaschromatography.Anal. Chem. 40, 1243-1246. HAMMER,