Journal of Analytical Toxicology, Vol. 16, September/October 1992
Concentrationof Cocaineand Metabolitesin Plasmaof Humans Following IntravenousAdministrationand Smoking of Cocaine D a n i e l S. I s e n s c h m i d
Southgate Medical Services, Inc., 21007 Southgate Park Blvd., Cleveland, Ohio 44137 M a r i a n W. F i s c h m a n a n d R i c h a r d W. F o l t i n
Johns Hopkins University, School of Medicine, Dept. of Psychiatry and Behavioral Sciences, Division of Behavioral Biology, The Houck Building, East-2, 600 N. Wolfe St., Baltimore, Maryland 21205 Y a l e H. C a p l a n
National Center for Forensic Science, 1901 Sulphur Spring Road, Baltimore, Maryland21227
l Abstract J Plasma was obtained from 10 human subjects at various intervals after administration of two rapid doses of cocaine, either intravenously or by smoking, and multiple doses by smoking and intravenously. The plasma was analyzed for COC and its metabolites, benzoylecgonlne (BE) and ecgonine methyl ester (EME). Plasma concentrations of COC were found to be dose-dependent. For patients receiving two successive doses of COC Intravenously (IV) or by smoking (SM), the average half-life of COC was found to be between 38 and 39 minutes, regardless of the dose or route of administration. Considerable Interindlvidual variation was observed. Multiple doses of both SM and IV COC were administered to three patients in a manner consistent with COC abuse. The maximum COC concentration observed was 1.2 mgJL following a total administration of 316 mg of COC over 90 min. Analysis of BE and EME confirmed that BE is the principle metabolite of COC In blood. All COC was accounted for by BE. EME, when present, did not exceed 5% of the BE concentration.
Introduction
Many investigators have studied the pharmacokinetics of cocaine (COC). However, most studies included only analysis of COC, with the exception of the study by Jeffcoat et al. (1), which included benzoylecgonine (BE). Despite evidence of significant quantities of ecgonine methyl ester (EME) in urine after COC administration (2), no pharmacokinetic studies have been performed that included EME as an analyte in blood. Since the pharmacokinetics of COC have been well documented, the purpose of this investigation was to obtain data using uniform methodology to define differences between in vivo COC metabolism and in vitro COC hydrolysis by analysis of COC, BE, and EME. The analysis of COC and metabolites in plasma after administration of two rapid IV or SM doses of COC was performed to determine if EME is a significant metabolite of COC in blood, as well as to study the rate of COC elimination from blood. Plasma samples were collected for a period of time after COC administration for the latter purpose. A limitation of typical pharmacokinetic studies is that only
single doses of drug are usually given. However, COC is often abused in a binge where several COC doses are administered over a relatively short period of time. The concentration of COC and metabolites following multiple doses of either SM or IV COC, as well as multiple doses by these two routes, was studied to determine typical plasma concentrations after a binge and to determine the concentration of metabolites present 24 h later. In addition to the pharmacokinetic data reported in this communication, acute tolerance and cardiovascular and subjective effects of COC in these patients was also studied and has been described elsewhere (3).
Materials and Methods
Human plasma specimens were obtained from Johns Hopkins University School of Medicine. The specimens were collected from 10 subjects with a known history of COC use. All subjects were inpatients at the Johns Hopkins Clinical Research Unit. Two rapid doses of IV or smoked cocaine. Ten subjects were given the following doses of COC on four separate study days, in various order: (1) Two doses of COC, 25 mg, SM, spaced 14 min apart; (2) two doses of COC, 50 mg, SM, spaced 14 min apart; (3) two doses of COC, 16 mg, IV, spaced 14 min apart; (4) two doses of COC, 32 mg, IV, spaced 14 min apart. Blood was collected at -20, 4, 18, 30, 44, 60, and 90 min, relative to the initial dose, in a grey top Vacutainer~ tube containing fluoride to reduce COC hydrolysis. Plasma was obtained after centrifugation and transferred to a glass tube that was capped and maintained at -15~ until analysis. Plasma specimens were thawed immediately prior to analysis for COC, BE, and EME. Multiple doses of mixed smoked and intravenous cocaine. Three subjects were given from 5-7 COC doses within 90 min. The amount of COC and the route of administration varied by day within the study. Blood was collected 20 min prior to administration of the first COC dose of the day and 18 and 88 min after the first dose, in a grey top Vacutainer tube containing fluoride to reduce COC hydrolysis. Plasma was obtained after cenWifugation and transferred to a glass tube that was capped and maintained at -15~ until analysis. Plasma specimens were thawed immediately prior to analysis for COC, BE, and EME.
Reproduction(photocopying)of editorialcontent of this journal is prohibited without publisher's permission.
311
Journal of Analytical Toxicology, Vol. 16,
Anah'sis. The procedure used for the extraction and quantitation of COC, BE, and EME has been described elsewhere (4).
R e s u l t s and D i s c u s s i o n
September~October1992
blood achieved after the final dose. The maximum blood COC concentration of 1.2 mg/L was obtained in a subject who smoked 50 mg COC six times within 70 min after receiving an initial IV injection of 16 mg COC. The average blood COC concentration in subjects after receiving a minimum of six doses of COC (50 mg, SM) within 90 min was 0.89 mg/L (range = 0.69-1.2 mg/L, N = 6). This concentration overlaps concentrations reported in sudden COC fatalities, where the average COC concentration was 0.60 mg/L (range = 0.10--0.90, N = 7) (6), although COC concentrations in most COC attributable fatalities are higher, averaging 3.0, 4.4, and 9.0 mg/L after IV, IN, and oral (PO) administration, respectively (7). It is noteworthy, however, that pattern of use on the street can yield blood COC concentrations that overlap with toxic COC concentrations. BE concentrations achieved in the blood after the last dose were simi/ar to the COC concentrations. The conversion of COC to BE is a dynamic process, and additional blood specimens after COC administration were not available. However, it is expected that the BE concentration would continue to rise before falling, reflecting the metabolism of the COC remaining after the last dose,
Concentration of cocaine and metabolites after two doses of cocaine The average COC and metabolite concentration for all subjects studied is shown in Table I. The average peak plasma COC concentration following administration of two doses each of 25 mg SM, 50 mg SM, 16 mg IV, and 32 mg IV were 0.21, 0.38, 0.23, and 0.47 mg/L, respectively. The average maximum BE concentrations were 0.20, 0_35, 0.24, and 0.40 mg/L. From this data it appears that most of the COC in the blood underwent conversion to BE, In addition, little or no EME was found in any of the specimens, suggesting that EME may not be a major metabolite of COC in blood. By doubling the COC dose, the average peak plasma COC concentration approximately doubled, suggesting that at the concenTable I. Concentration of Cocaine and Metabolites in Plasma Following Administration of Cocaine trations and route of administration studied, COC bioavailability does not appear to be Concentration(range) (mg/L) dose-dependent, although the bioavailability Time Dose COC BE EME of COC may be lower after SM than after IV (min) (mo) administration. Considerable variability in elfectiveness of smoking may occur between subjects and thus affect bioavailability by this route. Dose-dependent bioavailability has been documented primarily after intranasal (IN) administration of COC (5). Table 1I shows the elimination rate constant and half-life for COC by subject and their respective average by dose. The average halflife of COC, based on each subject, was determined to be between 38 and 39 rain for both the IV and SM route of administration, regardless of dosc. This is in contrast to the data of Jeffcoat et al., ( 1) which showed the half-life of COC to be 78 rain following a 20.5 mg IV dose, but is consistent with the data of Javaid et al., (5) in which the half-life of COC was determined to be 41 rain following a 32 mg IV dose. In addition, Jeffcoat et al. (1) reported that after smoking COC the half-life was 56 rain versus 78 and 80 min, respectively, after IV and IN COC administration. In the present study the half-lives for the 1V and SM routes were the same. Figures 1 and 2 show the average concentration of COC and BE for all subjects with time. The concentrations of COC and BE were equivalent between 30 and 40 min after the first dose, regardless of the route of administration and quantity of COC administered. The similar elimination curves obtained by both the IV and SM route confirm how similar effects may be seen via the IV or SM route of administration. Concentration of cocaine and metabolites following mixed doses of cocaine Table llI reports the COC concentrations in 312
-20 0 4 t4 18 30 44 60 90 -20 0 4 14 18 30 44 60 90 -20 0 4
14 18 30 44 60 90 -20 0 4 14 18 30 44 60 90
0.00
0.03 (0.00-0.09)
0.00
0,14 (0.05-029)
0.03 (0.00-0,07)
0.00
0.21 O15 0,12 0.09 006
0.08 0.13 0.16 0.20 0.19
0.00 0.00 0.00 (0.00-0.03) 0.01 (0.00-004) 0.02 (0.00-0.11)
25 8M 25 SM
(0,08-0.36) (0.06-026) (006-022) (005 0.17) (003-094)
(0.04-0.19) (0.61-0.21) (0.09-0.24) (0.11-0,33) (0.10-0.27)
0.00
0,02 (0,00-0.06)
000
0.22 (0,08-0.46)
003 (0,00-0.08)
0.00
0.38 0.28 0.21 0.16 0.12
0.11 0.21 0.28 0.31 0.35
(0.06-0.20) (0.13-0.35) (0.19-0.41) (0.23-0.51) (0.24-0.53)
0.00 0.01 0.01 0.02 0.02
0.00
0.01 (0.00-0.04)
0.00
0.12 (0.03-0.25)
0.02 (0.00-0.05)
0.00
0.23 0.18 0.12 0.10 0.07
0.09 0.16 0.20 0.23 0.24
0.00 0.00 0.00 0.00 (0.00-0,03) 0.00
50 SM 50 8M
(0.20-0,60) (0.19-O42) (O12 0.32) (096-026) (0.07-0,t8)
(0.00-0.03) (0.00-0.03) (0.00-0.04) (0.00-0.06)
16 IV 16 IV
32 IV
(0.13-0.34) (0.10-0.39) (0.08-0.18) (0.06-0.14) (004-0.11)
(0.06-0.15) (0.10-0.26) (0,13-0,29) (0.16-0.32) (0.16-0.34)
0.00
0.01 (0.00-0.04)
0.00
0.26 (0~13-0.36)
0.05 (0.03-0.07)
0.00
0,47 0,37 0.30 021 0.14
0,18 0.28 0.36 0,38 0,40
0,01 0.02 0.03 0.04 0.03
32 IV
(0,29-0.74) (8.23~,52) (0,16~,49) (0,09-039) (O07-021)
(0,12-0.24) (0,20-0,4~) (0,28-0,50) (0.26-0.58) (0.29-0.59)
(0,00-0.03) (0,00-0.06) (0,00-0.04) (0.03-0.06) (0.00-0.05)
COC = Cocaine; BE = Benzoylecgonine; EME = Ecgonine methyl ester: IV = intravenous; SM = smoked.
Journal of Analytical Toxicology, Vol. 16, September/October 1992
EME concentrations were very low, averaging 5.2% (range = 0--12.2%, N= 18) of the BE concentration (Table III). Baseline blood specimens collected from subjects 24 h after the last COC dose but prior to COC administration were positive for BE but negative for EME. The average BE concentration present in specimens collected from subjects who had received 250 mg or more COC the previous day was 0.13 mg/L (range = 0.08-0.15 mg/L, N = 4).
Conclusions
These studies confirmed that BE is the principal metabolite (in vivo) of COC in human blood. The average EME concentration, when present, was about 5% of the BE concentration. While EME had commonly been measured as a urinary metabolite of COC, no previous in vivo studies have measured the presence of this metabolite in blood. All reported measurements of EME in blood have been in postmortem specimens where specimen conditions between the time Table II. Elimination Rate and Half-Life of Cocaine in Plasma Following of death and time of analysis were often unAdministration of Cocaine known. Based on the data obtained in this study and data demonstrating that COC hyDose (mg) 32 IV drolyses to EME, not BE, in vitro in unpre25 SM 50 SM 16 IV served blood (8), it may be concluded that Subject k t,/, k t,/, k t,/, k t,/, EME arises primarily as a result of nonmetabolic (in vitro) hydrolysis of COC in 90 0.0102 68 0.0105 66 0.0142 49 0,0123 56 blood. The presence of significant quantities of 91 0.0250 28 0.0226 31 0.0200 35 0,0183 38 92 0.0227 31 0.0178 39 0.0258 27 0.0251 28 EME in urine is probably due to accumulation, 93 0.0147 47 0.0136 51 0.0165 42 0.0180 39 as hydrolysis of COC in the absence of serum 94 0.0245 28 0.0201 33 0.0192 36 enzymes results in its conversion to BE in 0.0264 26 95 0.0216 32 0.0242 29 0.0248 28 vitro. 96 0.0089 78 0.0080 87 0.0077 90 97 0.0178 39 0.0202 34 0.0211 33 0.0176 39 100 0.0172 40 0.0154 45 106 0.0134 52 0.0172 40 0.0134 52 Mean (1) (2)
0.0176 0.0206
39 34
0.0183 0.0203
38 34
39 34
0.0180 0.0211
0.0176 39 0.0187 37
Acknowledgment The Johns Hopkins Clinical Research Unit is supported by Grant #M01-RR-00035 from
(1) Based on each individual subject, haft-life calculated from k. (2) Based on the moan concentration (all subjects), half-life calculated from k. N = number; k = elimination rate constant; b/~ = half-life; SM = smoked.
25 MG, SM 0",1=9) 0.25
0.25
0.20
....+ .............................. +
0,15
0.20
' '+''''
0.10
"
16 MG, IV ~=10)
OJ5
P
0.10
...."+ 0.05
(=}
0.05
~: . . . . . ..-.- . . . . . ~< (c) -.-.','.', " . . . . . . . . . . . . . . . . . .
0.00
..." +" ........................
0.00
~o
20
30
4O
so
6o
70
eo
9o
~
u
~oo
10
20
30
40
50 60 MINUTES
MINUTES 50 MG. SM (N=-8)
O,40 i 0.351
....... -4- b)
0.30
.... -,1-.................
0
.
2
"&'""'"" 5
0.20 0.15 0.10
,,...,,....'
i
0.(;6 0.00 + 0
10
~, 20
u 30
40
)~
j ~ 50 60 MINUTES
70
80
~< 90
~,~
100
Figure 1. Concentrationof cocaine and metabolites after smoking two doses of cocaine14 rain apart; (a) cocaine; (b) benzoylecgonine;and (c) ecgonine methyl ester,
32 MG, IV 0q=8) o.5o 0.45 0.40 0.35 0.30 0.25 0.20 0.~5 .'"" ..,.'" 0.10 0.o5 +'" o.oo . 20
80
........
90
100
+
~
[aJ ...................
~
Concentrationof Cocaineand Metabolitesin Plasmaof Humans Following IntravenousAdministrationand Smoking of Cocaine D a n i e l S. I s e n s c h m i d
Southgate Medical Services, Inc., 21007 Southgate Park Blvd., Cleveland, Ohio 44137 M a r i a n W. F i s c h m a n a n d R i c h a r d W. F o l t i n
Johns Hopkins University, School of Medicine, Dept. of Psychiatry and Behavioral Sciences, Division of Behavioral Biology, The Houck Building, East-2, 600 N. Wolfe St., Baltimore, Maryland 21205 Y a l e H. C a p l a n
National Center for Forensic Science, 1901 Sulphur Spring Road, Baltimore, Maryland21227
l Abstract J Plasma was obtained from 10 human subjects at various intervals after administration of two rapid doses of cocaine, either intravenously or by smoking, and multiple doses by smoking and intravenously. The plasma was analyzed for COC and its metabolites, benzoylecgonlne (BE) and ecgonine methyl ester (EME). Plasma concentrations of COC were found to be dose-dependent. For patients receiving two successive doses of COC Intravenously (IV) or by smoking (SM), the average half-life of COC was found to be between 38 and 39 minutes, regardless of the dose or route of administration. Considerable Interindlvidual variation was observed. Multiple doses of both SM and IV COC were administered to three patients in a manner consistent with COC abuse. The maximum COC concentration observed was 1.2 mgJL following a total administration of 316 mg of COC over 90 min. Analysis of BE and EME confirmed that BE is the principle metabolite of COC In blood. All COC was accounted for by BE. EME, when present, did not exceed 5% of the BE concentration.
Introduction
Many investigators have studied the pharmacokinetics of cocaine (COC). However, most studies included only analysis of COC, with the exception of the study by Jeffcoat et al. (1), which included benzoylecgonine (BE). Despite evidence of significant quantities of ecgonine methyl ester (EME) in urine after COC administration (2), no pharmacokinetic studies have been performed that included EME as an analyte in blood. Since the pharmacokinetics of COC have been well documented, the purpose of this investigation was to obtain data using uniform methodology to define differences between in vivo COC metabolism and in vitro COC hydrolysis by analysis of COC, BE, and EME. The analysis of COC and metabolites in plasma after administration of two rapid IV or SM doses of COC was performed to determine if EME is a significant metabolite of COC in blood, as well as to study the rate of COC elimination from blood. Plasma samples were collected for a period of time after COC administration for the latter purpose. A limitation of typical pharmacokinetic studies is that only
single doses of drug are usually given. However, COC is often abused in a binge where several COC doses are administered over a relatively short period of time. The concentration of COC and metabolites following multiple doses of either SM or IV COC, as well as multiple doses by these two routes, was studied to determine typical plasma concentrations after a binge and to determine the concentration of metabolites present 24 h later. In addition to the pharmacokinetic data reported in this communication, acute tolerance and cardiovascular and subjective effects of COC in these patients was also studied and has been described elsewhere (3).
Materials and Methods
Human plasma specimens were obtained from Johns Hopkins University School of Medicine. The specimens were collected from 10 subjects with a known history of COC use. All subjects were inpatients at the Johns Hopkins Clinical Research Unit. Two rapid doses of IV or smoked cocaine. Ten subjects were given the following doses of COC on four separate study days, in various order: (1) Two doses of COC, 25 mg, SM, spaced 14 min apart; (2) two doses of COC, 50 mg, SM, spaced 14 min apart; (3) two doses of COC, 16 mg, IV, spaced 14 min apart; (4) two doses of COC, 32 mg, IV, spaced 14 min apart. Blood was collected at -20, 4, 18, 30, 44, 60, and 90 min, relative to the initial dose, in a grey top Vacutainer~ tube containing fluoride to reduce COC hydrolysis. Plasma was obtained after centrifugation and transferred to a glass tube that was capped and maintained at -15~ until analysis. Plasma specimens were thawed immediately prior to analysis for COC, BE, and EME. Multiple doses of mixed smoked and intravenous cocaine. Three subjects were given from 5-7 COC doses within 90 min. The amount of COC and the route of administration varied by day within the study. Blood was collected 20 min prior to administration of the first COC dose of the day and 18 and 88 min after the first dose, in a grey top Vacutainer tube containing fluoride to reduce COC hydrolysis. Plasma was obtained after cenWifugation and transferred to a glass tube that was capped and maintained at -15~ until analysis. Plasma specimens were thawed immediately prior to analysis for COC, BE, and EME.
Reproduction(photocopying)of editorialcontent of this journal is prohibited without publisher's permission.
311
Journal of Analytical Toxicology, Vol. 16,
Anah'sis. The procedure used for the extraction and quantitation of COC, BE, and EME has been described elsewhere (4).
R e s u l t s and D i s c u s s i o n
September~October1992
blood achieved after the final dose. The maximum blood COC concentration of 1.2 mg/L was obtained in a subject who smoked 50 mg COC six times within 70 min after receiving an initial IV injection of 16 mg COC. The average blood COC concentration in subjects after receiving a minimum of six doses of COC (50 mg, SM) within 90 min was 0.89 mg/L (range = 0.69-1.2 mg/L, N = 6). This concentration overlaps concentrations reported in sudden COC fatalities, where the average COC concentration was 0.60 mg/L (range = 0.10--0.90, N = 7) (6), although COC concentrations in most COC attributable fatalities are higher, averaging 3.0, 4.4, and 9.0 mg/L after IV, IN, and oral (PO) administration, respectively (7). It is noteworthy, however, that pattern of use on the street can yield blood COC concentrations that overlap with toxic COC concentrations. BE concentrations achieved in the blood after the last dose were simi/ar to the COC concentrations. The conversion of COC to BE is a dynamic process, and additional blood specimens after COC administration were not available. However, it is expected that the BE concentration would continue to rise before falling, reflecting the metabolism of the COC remaining after the last dose,
Concentration of cocaine and metabolites after two doses of cocaine The average COC and metabolite concentration for all subjects studied is shown in Table I. The average peak plasma COC concentration following administration of two doses each of 25 mg SM, 50 mg SM, 16 mg IV, and 32 mg IV were 0.21, 0.38, 0.23, and 0.47 mg/L, respectively. The average maximum BE concentrations were 0.20, 0_35, 0.24, and 0.40 mg/L. From this data it appears that most of the COC in the blood underwent conversion to BE, In addition, little or no EME was found in any of the specimens, suggesting that EME may not be a major metabolite of COC in blood. By doubling the COC dose, the average peak plasma COC concentration approximately doubled, suggesting that at the concenTable I. Concentration of Cocaine and Metabolites in Plasma Following Administration of Cocaine trations and route of administration studied, COC bioavailability does not appear to be Concentration(range) (mg/L) dose-dependent, although the bioavailability Time Dose COC BE EME of COC may be lower after SM than after IV (min) (mo) administration. Considerable variability in elfectiveness of smoking may occur between subjects and thus affect bioavailability by this route. Dose-dependent bioavailability has been documented primarily after intranasal (IN) administration of COC (5). Table 1I shows the elimination rate constant and half-life for COC by subject and their respective average by dose. The average halflife of COC, based on each subject, was determined to be between 38 and 39 rain for both the IV and SM route of administration, regardless of dosc. This is in contrast to the data of Jeffcoat et al., ( 1) which showed the half-life of COC to be 78 rain following a 20.5 mg IV dose, but is consistent with the data of Javaid et al., (5) in which the half-life of COC was determined to be 41 rain following a 32 mg IV dose. In addition, Jeffcoat et al. (1) reported that after smoking COC the half-life was 56 rain versus 78 and 80 min, respectively, after IV and IN COC administration. In the present study the half-lives for the 1V and SM routes were the same. Figures 1 and 2 show the average concentration of COC and BE for all subjects with time. The concentrations of COC and BE were equivalent between 30 and 40 min after the first dose, regardless of the route of administration and quantity of COC administered. The similar elimination curves obtained by both the IV and SM route confirm how similar effects may be seen via the IV or SM route of administration. Concentration of cocaine and metabolites following mixed doses of cocaine Table llI reports the COC concentrations in 312
-20 0 4 t4 18 30 44 60 90 -20 0 4 14 18 30 44 60 90 -20 0 4
14 18 30 44 60 90 -20 0 4 14 18 30 44 60 90
0.00
0.03 (0.00-0.09)
0.00
0,14 (0.05-029)
0.03 (0.00-0,07)
0.00
0.21 O15 0,12 0.09 006
0.08 0.13 0.16 0.20 0.19
0.00 0.00 0.00 (0.00-0.03) 0.01 (0.00-004) 0.02 (0.00-0.11)
25 8M 25 SM
(0,08-0.36) (0.06-026) (006-022) (005 0.17) (003-094)
(0.04-0.19) (0.61-0.21) (0.09-0.24) (0.11-0,33) (0.10-0.27)
0.00
0,02 (0,00-0.06)
000
0.22 (0,08-0.46)
003 (0,00-0.08)
0.00
0.38 0.28 0.21 0.16 0.12
0.11 0.21 0.28 0.31 0.35
(0.06-0.20) (0.13-0.35) (0.19-0.41) (0.23-0.51) (0.24-0.53)
0.00 0.01 0.01 0.02 0.02
0.00
0.01 (0.00-0.04)
0.00
0.12 (0.03-0.25)
0.02 (0.00-0.05)
0.00
0.23 0.18 0.12 0.10 0.07
0.09 0.16 0.20 0.23 0.24
0.00 0.00 0.00 0.00 (0.00-0,03) 0.00
50 SM 50 8M
(0.20-0,60) (0.19-O42) (O12 0.32) (096-026) (0.07-0,t8)
(0.00-0.03) (0.00-0.03) (0.00-0.04) (0.00-0.06)
16 IV 16 IV
32 IV
(0.13-0.34) (0.10-0.39) (0.08-0.18) (0.06-0.14) (004-0.11)
(0.06-0.15) (0.10-0.26) (0,13-0,29) (0.16-0.32) (0.16-0.34)
0.00
0.01 (0.00-0.04)
0.00
0.26 (0~13-0.36)
0.05 (0.03-0.07)
0.00
0,47 0,37 0.30 021 0.14
0,18 0.28 0.36 0,38 0,40
0,01 0.02 0.03 0.04 0.03
32 IV
(0,29-0.74) (8.23~,52) (0,16~,49) (0,09-039) (O07-021)
(0,12-0.24) (0,20-0,4~) (0,28-0,50) (0.26-0.58) (0.29-0.59)
(0,00-0.03) (0,00-0.06) (0,00-0.04) (0.03-0.06) (0.00-0.05)
COC = Cocaine; BE = Benzoylecgonine; EME = Ecgonine methyl ester: IV = intravenous; SM = smoked.
Journal of Analytical Toxicology, Vol. 16, September/October 1992
EME concentrations were very low, averaging 5.2% (range = 0--12.2%, N= 18) of the BE concentration (Table III). Baseline blood specimens collected from subjects 24 h after the last COC dose but prior to COC administration were positive for BE but negative for EME. The average BE concentration present in specimens collected from subjects who had received 250 mg or more COC the previous day was 0.13 mg/L (range = 0.08-0.15 mg/L, N = 4).
Conclusions
These studies confirmed that BE is the principal metabolite (in vivo) of COC in human blood. The average EME concentration, when present, was about 5% of the BE concentration. While EME had commonly been measured as a urinary metabolite of COC, no previous in vivo studies have measured the presence of this metabolite in blood. All reported measurements of EME in blood have been in postmortem specimens where specimen conditions between the time Table II. Elimination Rate and Half-Life of Cocaine in Plasma Following of death and time of analysis were often unAdministration of Cocaine known. Based on the data obtained in this study and data demonstrating that COC hyDose (mg) 32 IV drolyses to EME, not BE, in vitro in unpre25 SM 50 SM 16 IV served blood (8), it may be concluded that Subject k t,/, k t,/, k t,/, k t,/, EME arises primarily as a result of nonmetabolic (in vitro) hydrolysis of COC in 90 0.0102 68 0.0105 66 0.0142 49 0,0123 56 blood. The presence of significant quantities of 91 0.0250 28 0.0226 31 0.0200 35 0,0183 38 92 0.0227 31 0.0178 39 0.0258 27 0.0251 28 EME in urine is probably due to accumulation, 93 0.0147 47 0.0136 51 0.0165 42 0.0180 39 as hydrolysis of COC in the absence of serum 94 0.0245 28 0.0201 33 0.0192 36 enzymes results in its conversion to BE in 0.0264 26 95 0.0216 32 0.0242 29 0.0248 28 vitro. 96 0.0089 78 0.0080 87 0.0077 90 97 0.0178 39 0.0202 34 0.0211 33 0.0176 39 100 0.0172 40 0.0154 45 106 0.0134 52 0.0172 40 0.0134 52 Mean (1) (2)
0.0176 0.0206
39 34
0.0183 0.0203
38 34
39 34
0.0180 0.0211
0.0176 39 0.0187 37
Acknowledgment The Johns Hopkins Clinical Research Unit is supported by Grant #M01-RR-00035 from
(1) Based on each individual subject, haft-life calculated from k. (2) Based on the moan concentration (all subjects), half-life calculated from k. N = number; k = elimination rate constant; b/~ = half-life; SM = smoked.
25 MG, SM 0",1=9) 0.25
0.25
0.20
....+ .............................. +
0,15
0.20
' '+''''
0.10
"
16 MG, IV ~=10)
OJ5
P
0.10
...."+ 0.05
(=}
0.05
~: . . . . . ..-.- . . . . . ~< (c) -.-.','.', " . . . . . . . . . . . . . . . . . .
0.00
..." +" ........................
0.00
~o
20
30
4O
so
6o
70
eo
9o
~
u
~oo
10
20
30
40
50 60 MINUTES
MINUTES 50 MG. SM (N=-8)
O,40 i 0.351
....... -4- b)
0.30
.... -,1-.................
0
.
2
"&'""'"" 5
0.20 0.15 0.10
,,...,,....'
i
0.(;6 0.00 + 0
10
~, 20
u 30
40
)~
j ~ 50 60 MINUTES
70
80
~< 90
~,~
100
Figure 1. Concentrationof cocaine and metabolites after smoking two doses of cocaine14 rain apart; (a) cocaine; (b) benzoylecgonine;and (c) ecgonine methyl ester,
32 MG, IV 0q=8) o.5o 0.45 0.40 0.35 0.30 0.25 0.20 0.~5 .'"" ..,.'" 0.10 0.o5 +'" o.oo . 20
80
........
90
100
+
~
[aJ ...................
~
