- Email: [email protected]
Pharmacokinetics of Propylene Glycol in Humans During Multiple Dosing Regimens
Pharmacokinetics of Propylene Glycol in Humans During Multiple Dosing Regimens DALEK. Yu*, WILLIAM F. ELMQUIST, AND RONALD J. SAWCHUK‘ Received May 30, 1984, from the Department of Pharmaceutics, College of Pharmacy, Universi of Mmnesota, Minneapolis, MN 55455. Accepted for publication May 3, 1985. Present address: *BiopharmaceuticsUnit, Larion’Laboratories, Inc., Kansas City, MO
64137.
Abstract 3 The pharrnacokinetics of propylene glycol has been exam-
ined during multiple oral-dosing regimens. The glycol is rapidly absorbed, with Cp,, observed within 1 h following administration. The terminal elimination half-lifeis -4 h. After a minimum of 10 half-lives of maintenance dosing on a fixed regimen, the accumulation of propylene glycol differed significantly among individuals because of variability in apparent clearance. The average apparent total body clearance is -0.1 L kg . h and may be concentration dependent. The apparent volume of distribution is -0.5 L kg, approximating total body water.
Propylene glycol is a commonly used compound with diverse application. In the pharmaceutical industry the glycol is used as a solvent vehicle for drugs in oral solutions, injectables, and elixirs. It is also employed as a stabilizer for vitamins and as an emollient and humectant in ointment bases.’ After absorption, propylene glycol is metabolized to carbon dioxide and water through metabolic intermediates including lactic and pyruvic acids. In addition, a significant portion of the drug is excreted unchanged via the renal pathway.2One of the major reasons for the widespread use of propylene glycol is its apparent low systemic toxicity during chronic ingestion. Administration of propylene glycol to rats in oral doses as high as 13.3 mL/kg/d did not produce toxic effects on the kidney, heart, spleen, or liver.3 An intravenous LD50dose of 13 mL/kg and an oral LD5,, dose of 24 mL/kg have been identified in toxicity studies in rats.* However, a few cases of propylene glycol toxicity in humans during chronic ingestion have been reported recently. These include two children treated with vitamin preparations containing propylene glycol as a solvent. A 15-monthold child receiving 7.5 mL of propylene glycol daily as a vehicle for vitamin C therapy became stuporous, exhibiting tachypnea, tachycardia, and diaphoresis after 8 d. When the vitamin C preparation was discontinued, these symptoms quickly abated.5 An 11-year-old child receiving 2-4 mL of propylene glycol as a solvent for vitamin D twice daily developed grand ma1 seizures after 13 months. Despite treatment with anticonvulsants, the seizures persisted. Finally, when propylene glycol was replaced by ethanol and mediumchain triglycerides, the seizures terminated. Two additional cases of acute human intoxication involved a total intake of 60 mL of propylene glycol during vitamin D therapy. Both patients became stuporous and remained so for a number of hours.6 These incidents clearly indicate that propylene glycol, in contrast to common belief, may cause toxicity in humans. However, the pharmacokinetics of propylene glycol in humans has not been well described. Therefore, the present study was undertaken to investigate the pharmacokinetic behavior of propylene glycol in humans during multipledosing regimens in order to assess the degree of accumulation of this agent and the intersubject variability in its clearance. 876 /Journal of Pharmaceutical Sciences Vol. 74,No. 8,August 1985
Experimental Section Subjects in this study were all outpatients of the neurology clinic at the St. Paul Ramsey Medical Center who participated in a phenytoin bioavailability study.? The population included both males and females ranging in age from 18 to 65 years. Two separate studies were performed. Study I involved 16 patients who received 20 mL (20.7g) of propylene glycol every 8 h as a solvent in a sodium phenytoin oral solution. Study I1 was conducted with six additional patients who received 40 mL (41.4g) of propylene glycol every 12 h in conjunction with the oral phenytoin formulation. Patients were maintained on this formulation for a minimum of 3 d, (after data analysis this period was found to correspond to a minimum of 10 half-lives of the glycol) before having serial blood samples drawn a t steady state. On the day prior to serial sampling, blood samples were drawn just before dosing to allow an assessment of the variability of steady-state trough levels during the treatment period. Patients were also observed for signs of nystagmus, ataxia, and mental symptoms during the same treatment period. The oral formulation containing 100 mg of sodium phenytoin included 20 mL of propylene glycol USP, 7.25mL of alcohol USP, 6 pL of Peach Flavor Imitation (Fries), 5 mL of glycerin USP, 8 mL of Finn Fructose (Liquid Fructose 70%, w/w), and sufficient distilled water to make the final volume 50 mL.7 In both studies, the patients received the dose of the formulation under study, followed by 6 ounces (175mL) of water. Serial blood sampling was performed via a “heparin lock” over the 8-h dosing interval in study I and over the 12-h interval in study 11. Sampling times were 0, 1,2,3,4,6, and 8 h in study I, with an additional sample drawn by venipuncture at 12 h in study 11. All blood samples were collected in heparinized Vacutainer tubes, centrifuged, and the plasma samples were frozen until analysis. A gas-liquid chromatographic assay recently developed in our laboratorys was used to analyze propylene glycol in the patient plasma samples. The analysis was performed using a HewlettPackard 5830A GC equipped with a flame-ionization detector.
Results and Discussion The elimination half-life (tl,z) was estimated by using nonlinear regression to fit a monoexponential equation to plasma concentration-time data 2 h postadministration. Area under the plasma concentration-time curve (AUC) over one dosing interval was calculated using actual times rather than nominal times when there was a difference. The AUC over the dosing interval was calculated by two methods. The first method assumed that all patients were a t steady state and utilized the trapezoidal rule to calculate the area over the dosing interval ([email protected] second method, which did not assume the existence of a steady state (AUC,,,), involved the use of the following relationship to calculate the AUC,,,:
AUC,,,
=
AUC;
- CPO + CPT kd
where Cp, and Cp, are the plasma concentrations of propylene glycol at the first and last sampling time during the 0022-3549/85/0800-0876$0 1.OO/O 0 1985,American Pharmaceutical Association
dosing interval, respectively. The elimination rate constant, kd, corresponds to the half-life determined from the terminal portion of the plasma concentration-time curve. The apparent total body clearance was calculated using both steadystate (TBCLJF) and non-steady-state assumptions (TBCL,,,/F). The following equations were used to calculate these parameters: -TBCL,, =-
D AUCZ
F
where D is the maintenance dose and F is the bioavailability. The CPT - Cpdkd term in the denominator Of eq. corrects the AUC for differences in trough concentrations that would be seen in a non-steady-state situation. The apparent volume of distribution was calculated using the following equation:
-V_d
TBCL,,, kdF
-
F
(4)
Figures 1 and 2 show weight-normalized average plasma concentrations ( 5 SD) of propylene glycol following an oral maintenance dose in studies I and 11, respectively. Propylene glycol concentrations appeared to peak within 1 h postadministration, followed by an apparent monoexponential decline in concentration as a function of time. The average terminal half-lives in studies I and I1 were 3.8 and 4.1 h, respectively. Since the original purpose of the study was to examine the bioavailability of various dosage forms of phenytoin a t steady state,' there were insufficient data during the early part of the interval to characterize the absorption rate of propylene glycol in humans. Tables I and I1 list the pharmacokinetic parameters of the patients in studies I and 11, respectively. Although it is likely that propylene glycol, an aliphatic alcohol, is completely absorbed into the systemic circulation: no direct evidence of this is available. and thus no value for F was assumed. The validity of the steady-state assumption was questioned initially because of the observation that, on the day of serial sampling, the cp,levels were generally higher than the cp, levels in most of the subjects. H ~no significant ~ differ~
Table I-Pharmacokinetic Parameters of Propylene Glycol in Humans Determined over One Dosing Interval during Oral Maintenance Dosing in Study la AUC,,,
TBCL,,IF,
AUC,,
Sub)ect rnghirnL rng.h/mL
loo[ 70
t
T
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
I '
51
'
0
2
4
6
8
Time, h
Flgure 1- glycol Weight-normalized average plasma concentration (2 SO)of propylene over one dosing interval fol/owing an oral maintenance dose in study I (20.7 g three times daily).
X
SD
c
TBCL,,$F,
t112r
Uh.kg
Llh.kg
VdlF, Ukg 0.55 0.73 0.55 0.48 0.67 0.69 0.50 0.67 0.50 0.55 0.61 0.44 0.77 0.41 0.61 0.59
3.45 3.35 2.98 2.09 4.03 3.25 3.12 2.69 3.40 1.77 2.34 2.42 5.07 5.25 3.04 3.31
3.35 3.26 2.64 2.43 3.60 3.25 3.07 2.57 3.44 1.86 2.65 2.50 3.31 5.26 2.65 3.17
3.70 4.49 3.07 3.26 4.02 4.41 3.57 4.34 3.46 2.39 4.87 2.83 5.22 4.37 3.50 3.14
0.099 0.110 0.109 0.119 0.103 0.107 0.096 0.102 0.103 0.168 0.099 0.112 0.067 0.065 0.106 0.125
0.102 0.113 0.124 0.102 0.115 0.109 0.097 0.107 0.101 0.159 0.087 0.108 0.102 0.065 0.121 0.131
3.23 0.95
3.06 0.75
3.79 0.78
0.106 0.023
0.109 0.020
0.58 0.10 _ _ I -
a
Dose was 20.7 g three times daily.
l50r 100
I
t
1
70r
-
Table 11-Pharmacokinetic Parameters of Propylene Glycol in Humans Determined Over One Dosing Interval During Oral Maintenance Dosing in Study Ila
50[
T 19 20 21 22 23 24
i
1 1 0 L
l.1 '
Pre
'
0
TBCL,,IF,
AUC,,,, AUC,,, mg . h/mL mg . hlmL
T
2
4
6
8
10
12
Time, h
-
(*
Figure 2- Weight-normalized average plasma concentration SO)of propylene glycol following a single oral maintenance dose in study /I (41.4 g two times daily).
~
X
SD a
L/h . kg
L/h kg
.
VdIF, Likg
TBCL,,,IF,
5.48 11.98 8.15 8.66 6.13 6.05
4.89 10.25 8.09 8.47 6.03 5.15
4.44 4.01 4.50 3.63 2.98 5.05
0.086 0.060 0.059 0.092 0.078 0.096
0.096 0.070 0.060 0.095 0.080 0.113
0.62 0.40 0.39 0.50 0.36 0.82
7.74 2.43
7.15 2.13
4.10 0.66
0.079 0.015
0.086 0.018
0.52 0.16
Dose was 41.4 g two times daily.
Journal of Pharmaceutical Sciences / 877 Vol. 74, No. 8, August 1.985
ence was observed in the estimates of TBCLJF and TBCL,,,,/F in study I (p > 0.05). In study 11, all six patients had Cp, levels higher than the Cp, levels; accordingly, TBCL,,,/F was significantly larger than TBCL,,/F in these patients (p < 0.05). It is conceivable that circadian alterations in clearance or rate of absorption of the glycol may give rise to differences in consecutive trough plasma levels if the dosing interval is phased with a fluctuating clearance or absorption rate. In addition, a non-steady-state may exist because of dose-to-dose differences in the maintenance dose or dosing interval. Here, TBCL,,,/F should provide a more accurate estimate of the clearance than TBCL,,/F because it is estimated without an assumption of steady state. The apparent TBCL,,,, estimates varied over a relatively large range among patients in both studies (CV = 18.62 and 20.93%in studies J and 11, respectively). The extent of this variation is apparent when the plasma concentration-time data of subject #11 (lowest overall propylene glycol concentrations) are compared to those of subject #15 (highest), as shown in Fig. 3. The body-weight-normalized time-averaged plasma concentration of propylene glycol in patients #15 and #11 were 39.85 and 15.42 mg. kg/mL, respectively; thus, there is a 2.6-fold difference in concentration. Similar interpatient variability in apparent total body clearance was also
2
E 0)
E ri 0
0
Time. h
Figure 3-Plasma concentration-time profile for propylene glycol in patients # 1 1 and #15 over one dosing interval following an oral maintenance dose in study I of 20.7 g, Key: (A)patient # 15;( 0 )patient #11.
??i
Figure 4-Plasma concentration-time profile for propylene glycol in patients #20 and #24 fol!uwing a single oral maintenance dose in study I1 of 41.4 g. Key: (A)patient #20; ( 0 )patient #24.
878 Journal of Pharmaceutical Sciences Vol. 74, No. 8, August 1985
observed in study 11, with the extremes depicted in Fig. 4. It is possible that some of the observed variability in apparent clearance may be due to interpatient differences in bioavailability, although it is expected that this variability would be less than that associated with the total body clearance of propylene glycol. The time-averaged concentrations of propylene glycol in patients #20 and #24 were 49.3 and 35.9 mg * kg/mL, respectively. The variation in apparent clearance indicates that some patients may be more susceptible to propylene glycol accumulation and possible central nervous system (CNS) toxicity or other toxicity. A significant segment of each patient group showed various degrees of CNS toxicity that were not caused by phenytoin.7 Although one may speculate that these CNS effects are related to the average plasma concentrations of propylene glycol over the dosing interval, there was no clear relationship between plasma concentration and CNS toxicity in these studies. Patient #22 in study I1 demonstrated the most severe mental symptoms; the apparent Cp,,, was 1.52 mg/mL (the highest Cp,,, in this study was 2.05 mg/mL) and the corresponding trough level was -0.3 mg/mL. A similar degree of CNS toxicity was observed in patient #24, even though this patient exhibited the lowest overall propylene glycol plasma concentrations in study 11. In study I, patient #15 suffered severe mental symptoms which may be related to his highest overall plasma concentrations, although patients with lower concentrations also showed similar CNS toxicity. Individual patient sensitivity to propylene glycol may be important in determining propylene glycol toxicity. In any case, the toxicity of propylene glycol is evidenced by the observation that these CNS symptoms occurred only in patients when they were ingesting the phenytoin oral solution, not the capsules.? This finding confirms other reports of propylene glycol intoxication in humans described previousiy.5.6 The average TBCL,,,IF estimate in study I is significantly higher than that in study I1 (p < 0.051, indicating that, in the dosage range studied, the apparent total body clearance may be concentration dependent. Similar results were also observed in a study of the pharmacokinetics of propylene glycol in the rabbit.1° The average apparent volumes of distribution were 0.58 and 0.52 L/kg in study I and study 11,respectively. There is no significant difference between the two estimates (p > 0.05). This value approximates total body water reasonably well, suggesting that the bioavailability of propylene glycol may be close to complete. It may be concluded that, like ethano1,ll propylene glycol is free to distribute uniformly into total body water without significant distribution to specific tissues. There is also wide variability in the apparent volume estimates among patients, which can partially explain the interpatient plasma concentration differences. Incomplete bioavailability, if it occurs, could also contribute to the observed variability in the apparent clearance. The average half-life estimates are 3.8 and 4.1 h for study I and study 11, respectively (p > 0.051, with an overall range of 2.4-5.2 h. For a regimen which involves a dosing interval of 8 h, it is expected that propylene glycol accumulation would result in peak plasma concentrations at steady state that are from 10 to 50% greater than those observed following the first dose. Where doses of 20 g or more are involved, peak plasma levels in the range of 0.5-2 mg/mL may be expected. In conclusion, these studies demonstrate that there is measurable accumulation of propylene glycol in patients who ingest it in conjunction with multiple-dosing regimens. As an aliphatic alcohol, propylene glycol can cause CNS depressant effects similar to ethanol, although three times the dose is required to cause the same degree of narcosis.12 The CNS depressant effect of ethanol becomes marked when concentrations rise above 1 mg/mL.13The propylene glycol concen-
References and Notes
3. Seidenfeld, M. A.; Hanzlik, P. J. J. Pharmacol. Exp. Ther. 1932, 44, 109-121. 4. Ruddick, J. A. Toxicol. Appl. Pharmacol. 1972,21, 102-111. 5. Martin, G,; Finberg, L. J . pediatr, 1970, 77, 877-878. 6. Arulantham, K.; Genel, M. J . Pediutr. 1 9 7 8 , 9 3 , 5 1 5 - ~ 6 . 7. Sawchuk, R. J.; Pepin, S. M.; Leppik, I. E.; Gumnit, R. J. J . Phnrmacoktnet. Biopharm. 1982,10, 365-382. 8. Yu. D. K.: Sawchuk. R. J. Clin. Chem. 1983.29.2088-2090. 9. Cooke, A.’R.; Birchall, A. Gastroenterology 1969, 57, 269-272. 10. Yu, D. K., Ph.D. Thesis; University of Minnesota, 1984. 11. Ritchie, J. M. in “The Pharmacological Basis of Therapeutics”; Goodman, L. S.; Gilman, A., Eds.; Macmillan: New York, 1966;p
1. Heine, D. L.; Parker, P. F.; Francke, D. E. Bull. A m . Soc. Hosp. Pharm. 1950, 7,8-17. 2. Van Winkel, W. J. J . Pharmacol. Exp. Ther. 1941, 72,344-353.
12. Llkman, A. J.; Newman, H. W. J . Pharmacol. Ezp. Ther. 1937, 60,312-322. 13. David, D. J.;Spyker, D. A. Vet. Hum. Toxicol. 1979,21,272-276.
tration ranges observed in this study demonstrate that the accumulation of propylene glycol in humans during multiple dosing is significant enough to cause toxic effects. Moreover, some patients appear to be more susceptible to the effects of this agent. The use of propylene glycol as a solvent in longterm drug therapy needs to be further evaluated.
1 AQ
Journal of Pharmaceufical Sciences / 879 Vol. 74, No. 8, August 1985
64137.
Abstract 3 The pharrnacokinetics of propylene glycol has been exam-
ined during multiple oral-dosing regimens. The glycol is rapidly absorbed, with Cp,, observed within 1 h following administration. The terminal elimination half-lifeis -4 h. After a minimum of 10 half-lives of maintenance dosing on a fixed regimen, the accumulation of propylene glycol differed significantly among individuals because of variability in apparent clearance. The average apparent total body clearance is -0.1 L kg . h and may be concentration dependent. The apparent volume of distribution is -0.5 L kg, approximating total body water.
Propylene glycol is a commonly used compound with diverse application. In the pharmaceutical industry the glycol is used as a solvent vehicle for drugs in oral solutions, injectables, and elixirs. It is also employed as a stabilizer for vitamins and as an emollient and humectant in ointment bases.’ After absorption, propylene glycol is metabolized to carbon dioxide and water through metabolic intermediates including lactic and pyruvic acids. In addition, a significant portion of the drug is excreted unchanged via the renal pathway.2One of the major reasons for the widespread use of propylene glycol is its apparent low systemic toxicity during chronic ingestion. Administration of propylene glycol to rats in oral doses as high as 13.3 mL/kg/d did not produce toxic effects on the kidney, heart, spleen, or liver.3 An intravenous LD50dose of 13 mL/kg and an oral LD5,, dose of 24 mL/kg have been identified in toxicity studies in rats.* However, a few cases of propylene glycol toxicity in humans during chronic ingestion have been reported recently. These include two children treated with vitamin preparations containing propylene glycol as a solvent. A 15-monthold child receiving 7.5 mL of propylene glycol daily as a vehicle for vitamin C therapy became stuporous, exhibiting tachypnea, tachycardia, and diaphoresis after 8 d. When the vitamin C preparation was discontinued, these symptoms quickly abated.5 An 11-year-old child receiving 2-4 mL of propylene glycol as a solvent for vitamin D twice daily developed grand ma1 seizures after 13 months. Despite treatment with anticonvulsants, the seizures persisted. Finally, when propylene glycol was replaced by ethanol and mediumchain triglycerides, the seizures terminated. Two additional cases of acute human intoxication involved a total intake of 60 mL of propylene glycol during vitamin D therapy. Both patients became stuporous and remained so for a number of hours.6 These incidents clearly indicate that propylene glycol, in contrast to common belief, may cause toxicity in humans. However, the pharmacokinetics of propylene glycol in humans has not been well described. Therefore, the present study was undertaken to investigate the pharmacokinetic behavior of propylene glycol in humans during multipledosing regimens in order to assess the degree of accumulation of this agent and the intersubject variability in its clearance. 876 /Journal of Pharmaceutical Sciences Vol. 74,No. 8,August 1985
Experimental Section Subjects in this study were all outpatients of the neurology clinic at the St. Paul Ramsey Medical Center who participated in a phenytoin bioavailability study.? The population included both males and females ranging in age from 18 to 65 years. Two separate studies were performed. Study I involved 16 patients who received 20 mL (20.7g) of propylene glycol every 8 h as a solvent in a sodium phenytoin oral solution. Study I1 was conducted with six additional patients who received 40 mL (41.4g) of propylene glycol every 12 h in conjunction with the oral phenytoin formulation. Patients were maintained on this formulation for a minimum of 3 d, (after data analysis this period was found to correspond to a minimum of 10 half-lives of the glycol) before having serial blood samples drawn a t steady state. On the day prior to serial sampling, blood samples were drawn just before dosing to allow an assessment of the variability of steady-state trough levels during the treatment period. Patients were also observed for signs of nystagmus, ataxia, and mental symptoms during the same treatment period. The oral formulation containing 100 mg of sodium phenytoin included 20 mL of propylene glycol USP, 7.25mL of alcohol USP, 6 pL of Peach Flavor Imitation (Fries), 5 mL of glycerin USP, 8 mL of Finn Fructose (Liquid Fructose 70%, w/w), and sufficient distilled water to make the final volume 50 mL.7 In both studies, the patients received the dose of the formulation under study, followed by 6 ounces (175mL) of water. Serial blood sampling was performed via a “heparin lock” over the 8-h dosing interval in study I and over the 12-h interval in study 11. Sampling times were 0, 1,2,3,4,6, and 8 h in study I, with an additional sample drawn by venipuncture at 12 h in study 11. All blood samples were collected in heparinized Vacutainer tubes, centrifuged, and the plasma samples were frozen until analysis. A gas-liquid chromatographic assay recently developed in our laboratorys was used to analyze propylene glycol in the patient plasma samples. The analysis was performed using a HewlettPackard 5830A GC equipped with a flame-ionization detector.
Results and Discussion The elimination half-life (tl,z) was estimated by using nonlinear regression to fit a monoexponential equation to plasma concentration-time data 2 h postadministration. Area under the plasma concentration-time curve (AUC) over one dosing interval was calculated using actual times rather than nominal times when there was a difference. The AUC over the dosing interval was calculated by two methods. The first method assumed that all patients were a t steady state and utilized the trapezoidal rule to calculate the area over the dosing interval ([email protected] second method, which did not assume the existence of a steady state (AUC,,,), involved the use of the following relationship to calculate the AUC,,,:
AUC,,,
=
AUC;
- CPO + CPT kd
where Cp, and Cp, are the plasma concentrations of propylene glycol at the first and last sampling time during the 0022-3549/85/0800-0876$0 1.OO/O 0 1985,American Pharmaceutical Association
dosing interval, respectively. The elimination rate constant, kd, corresponds to the half-life determined from the terminal portion of the plasma concentration-time curve. The apparent total body clearance was calculated using both steadystate (TBCLJF) and non-steady-state assumptions (TBCL,,,/F). The following equations were used to calculate these parameters: -TBCL,, =-
D AUCZ
F
where D is the maintenance dose and F is the bioavailability. The CPT - Cpdkd term in the denominator Of eq. corrects the AUC for differences in trough concentrations that would be seen in a non-steady-state situation. The apparent volume of distribution was calculated using the following equation:
-V_d
TBCL,,, kdF
-
F
(4)
Figures 1 and 2 show weight-normalized average plasma concentrations ( 5 SD) of propylene glycol following an oral maintenance dose in studies I and 11, respectively. Propylene glycol concentrations appeared to peak within 1 h postadministration, followed by an apparent monoexponential decline in concentration as a function of time. The average terminal half-lives in studies I and I1 were 3.8 and 4.1 h, respectively. Since the original purpose of the study was to examine the bioavailability of various dosage forms of phenytoin a t steady state,' there were insufficient data during the early part of the interval to characterize the absorption rate of propylene glycol in humans. Tables I and I1 list the pharmacokinetic parameters of the patients in studies I and 11, respectively. Although it is likely that propylene glycol, an aliphatic alcohol, is completely absorbed into the systemic circulation: no direct evidence of this is available. and thus no value for F was assumed. The validity of the steady-state assumption was questioned initially because of the observation that, on the day of serial sampling, the cp,levels were generally higher than the cp, levels in most of the subjects. H ~no significant ~ differ~
Table I-Pharmacokinetic Parameters of Propylene Glycol in Humans Determined over One Dosing Interval during Oral Maintenance Dosing in Study la AUC,,,
TBCL,,IF,
AUC,,
Sub)ect rnghirnL rng.h/mL
loo[ 70
t
T
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
I '
51
'
0
2
4
6
8
Time, h
Flgure 1- glycol Weight-normalized average plasma concentration (2 SO)of propylene over one dosing interval fol/owing an oral maintenance dose in study I (20.7 g three times daily).
X
SD
c
TBCL,,$F,
t112r
Uh.kg
Llh.kg
VdlF, Ukg 0.55 0.73 0.55 0.48 0.67 0.69 0.50 0.67 0.50 0.55 0.61 0.44 0.77 0.41 0.61 0.59
3.45 3.35 2.98 2.09 4.03 3.25 3.12 2.69 3.40 1.77 2.34 2.42 5.07 5.25 3.04 3.31
3.35 3.26 2.64 2.43 3.60 3.25 3.07 2.57 3.44 1.86 2.65 2.50 3.31 5.26 2.65 3.17
3.70 4.49 3.07 3.26 4.02 4.41 3.57 4.34 3.46 2.39 4.87 2.83 5.22 4.37 3.50 3.14
0.099 0.110 0.109 0.119 0.103 0.107 0.096 0.102 0.103 0.168 0.099 0.112 0.067 0.065 0.106 0.125
0.102 0.113 0.124 0.102 0.115 0.109 0.097 0.107 0.101 0.159 0.087 0.108 0.102 0.065 0.121 0.131
3.23 0.95
3.06 0.75
3.79 0.78
0.106 0.023
0.109 0.020
0.58 0.10 _ _ I -
a
Dose was 20.7 g three times daily.
l50r 100
I
t
1
70r
-
Table 11-Pharmacokinetic Parameters of Propylene Glycol in Humans Determined Over One Dosing Interval During Oral Maintenance Dosing in Study Ila
50[
T 19 20 21 22 23 24
i
1 1 0 L
l.1 '
Pre
'
0
TBCL,,IF,
AUC,,,, AUC,,, mg . h/mL mg . hlmL
T
2
4
6
8
10
12
Time, h
-
(*
Figure 2- Weight-normalized average plasma concentration SO)of propylene glycol following a single oral maintenance dose in study /I (41.4 g two times daily).
~
X
SD a
L/h . kg
L/h kg
.
VdIF, Likg
TBCL,,,IF,
5.48 11.98 8.15 8.66 6.13 6.05
4.89 10.25 8.09 8.47 6.03 5.15
4.44 4.01 4.50 3.63 2.98 5.05
0.086 0.060 0.059 0.092 0.078 0.096
0.096 0.070 0.060 0.095 0.080 0.113
0.62 0.40 0.39 0.50 0.36 0.82
7.74 2.43
7.15 2.13
4.10 0.66
0.079 0.015
0.086 0.018
0.52 0.16
Dose was 41.4 g two times daily.
Journal of Pharmaceutical Sciences / 877 Vol. 74, No. 8, August 1.985
ence was observed in the estimates of TBCLJF and TBCL,,,,/F in study I (p > 0.05). In study 11, all six patients had Cp, levels higher than the Cp, levels; accordingly, TBCL,,,/F was significantly larger than TBCL,,/F in these patients (p < 0.05). It is conceivable that circadian alterations in clearance or rate of absorption of the glycol may give rise to differences in consecutive trough plasma levels if the dosing interval is phased with a fluctuating clearance or absorption rate. In addition, a non-steady-state may exist because of dose-to-dose differences in the maintenance dose or dosing interval. Here, TBCL,,,/F should provide a more accurate estimate of the clearance than TBCL,,/F because it is estimated without an assumption of steady state. The apparent TBCL,,,, estimates varied over a relatively large range among patients in both studies (CV = 18.62 and 20.93%in studies J and 11, respectively). The extent of this variation is apparent when the plasma concentration-time data of subject #11 (lowest overall propylene glycol concentrations) are compared to those of subject #15 (highest), as shown in Fig. 3. The body-weight-normalized time-averaged plasma concentration of propylene glycol in patients #15 and #11 were 39.85 and 15.42 mg. kg/mL, respectively; thus, there is a 2.6-fold difference in concentration. Similar interpatient variability in apparent total body clearance was also
2
E 0)
E ri 0
0
Time. h
Figure 3-Plasma concentration-time profile for propylene glycol in patients # 1 1 and #15 over one dosing interval following an oral maintenance dose in study I of 20.7 g, Key: (A)patient # 15;( 0 )patient #11.
??i
Figure 4-Plasma concentration-time profile for propylene glycol in patients #20 and #24 fol!uwing a single oral maintenance dose in study I1 of 41.4 g. Key: (A)patient #20; ( 0 )patient #24.
878 Journal of Pharmaceutical Sciences Vol. 74, No. 8, August 1985
observed in study 11, with the extremes depicted in Fig. 4. It is possible that some of the observed variability in apparent clearance may be due to interpatient differences in bioavailability, although it is expected that this variability would be less than that associated with the total body clearance of propylene glycol. The time-averaged concentrations of propylene glycol in patients #20 and #24 were 49.3 and 35.9 mg * kg/mL, respectively. The variation in apparent clearance indicates that some patients may be more susceptible to propylene glycol accumulation and possible central nervous system (CNS) toxicity or other toxicity. A significant segment of each patient group showed various degrees of CNS toxicity that were not caused by phenytoin.7 Although one may speculate that these CNS effects are related to the average plasma concentrations of propylene glycol over the dosing interval, there was no clear relationship between plasma concentration and CNS toxicity in these studies. Patient #22 in study I1 demonstrated the most severe mental symptoms; the apparent Cp,,, was 1.52 mg/mL (the highest Cp,,, in this study was 2.05 mg/mL) and the corresponding trough level was -0.3 mg/mL. A similar degree of CNS toxicity was observed in patient #24, even though this patient exhibited the lowest overall propylene glycol plasma concentrations in study 11. In study I, patient #15 suffered severe mental symptoms which may be related to his highest overall plasma concentrations, although patients with lower concentrations also showed similar CNS toxicity. Individual patient sensitivity to propylene glycol may be important in determining propylene glycol toxicity. In any case, the toxicity of propylene glycol is evidenced by the observation that these CNS symptoms occurred only in patients when they were ingesting the phenytoin oral solution, not the capsules.? This finding confirms other reports of propylene glycol intoxication in humans described previousiy.5.6 The average TBCL,,,IF estimate in study I is significantly higher than that in study I1 (p < 0.051, indicating that, in the dosage range studied, the apparent total body clearance may be concentration dependent. Similar results were also observed in a study of the pharmacokinetics of propylene glycol in the rabbit.1° The average apparent volumes of distribution were 0.58 and 0.52 L/kg in study I and study 11,respectively. There is no significant difference between the two estimates (p > 0.05). This value approximates total body water reasonably well, suggesting that the bioavailability of propylene glycol may be close to complete. It may be concluded that, like ethano1,ll propylene glycol is free to distribute uniformly into total body water without significant distribution to specific tissues. There is also wide variability in the apparent volume estimates among patients, which can partially explain the interpatient plasma concentration differences. Incomplete bioavailability, if it occurs, could also contribute to the observed variability in the apparent clearance. The average half-life estimates are 3.8 and 4.1 h for study I and study 11, respectively (p > 0.051, with an overall range of 2.4-5.2 h. For a regimen which involves a dosing interval of 8 h, it is expected that propylene glycol accumulation would result in peak plasma concentrations at steady state that are from 10 to 50% greater than those observed following the first dose. Where doses of 20 g or more are involved, peak plasma levels in the range of 0.5-2 mg/mL may be expected. In conclusion, these studies demonstrate that there is measurable accumulation of propylene glycol in patients who ingest it in conjunction with multiple-dosing regimens. As an aliphatic alcohol, propylene glycol can cause CNS depressant effects similar to ethanol, although three times the dose is required to cause the same degree of narcosis.12 The CNS depressant effect of ethanol becomes marked when concentrations rise above 1 mg/mL.13The propylene glycol concen-
References and Notes
3. Seidenfeld, M. A.; Hanzlik, P. J. J. Pharmacol. Exp. Ther. 1932, 44, 109-121. 4. Ruddick, J. A. Toxicol. Appl. Pharmacol. 1972,21, 102-111. 5. Martin, G,; Finberg, L. J . pediatr, 1970, 77, 877-878. 6. Arulantham, K.; Genel, M. J . Pediutr. 1 9 7 8 , 9 3 , 5 1 5 - ~ 6 . 7. Sawchuk, R. J.; Pepin, S. M.; Leppik, I. E.; Gumnit, R. J. J . Phnrmacoktnet. Biopharm. 1982,10, 365-382. 8. Yu. D. K.: Sawchuk. R. J. Clin. Chem. 1983.29.2088-2090. 9. Cooke, A.’R.; Birchall, A. Gastroenterology 1969, 57, 269-272. 10. Yu, D. K., Ph.D. Thesis; University of Minnesota, 1984. 11. Ritchie, J. M. in “The Pharmacological Basis of Therapeutics”; Goodman, L. S.; Gilman, A., Eds.; Macmillan: New York, 1966;p
1. Heine, D. L.; Parker, P. F.; Francke, D. E. Bull. A m . Soc. Hosp. Pharm. 1950, 7,8-17. 2. Van Winkel, W. J. J . Pharmacol. Exp. Ther. 1941, 72,344-353.
12. Llkman, A. J.; Newman, H. W. J . Pharmacol. Ezp. Ther. 1937, 60,312-322. 13. David, D. J.;Spyker, D. A. Vet. Hum. Toxicol. 1979,21,272-276.
tration ranges observed in this study demonstrate that the accumulation of propylene glycol in humans during multiple dosing is significant enough to cause toxic effects. Moreover, some patients appear to be more susceptible to the effects of this agent. The use of propylene glycol as a solvent in longterm drug therapy needs to be further evaluated.
1 AQ
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