IPSIndian Journal of Pharmacology
Home  IPS  Feedback Subscribe Top cited articles Login 
Users Online : 1234 
Small font sizeDefault font sizeIncrease font size
Navigate Here
  Search
 
  
Resource Links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (564 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)

 
In This Article
 »  Abstract
 » Introduction
 »  Materials and Me...
 » Blood Sampling
 » Results
 » Discussion
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed2686    
    Printed91    
    Emailed1    
    PDF Downloaded146    
    Comments [Add]    
    Cited by others 2    

Recommend this journal

 


 
 Table of Contents    
SHORT COMMUNICATION
Year : 2012  |  Volume : 44  |  Issue : 3  |  Page : 402-406
 

Propofol pharmacokinetics in young healthy Indian subjects


1 Department of Anesthesia, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 University Institute of Pharmaceutical Sciences Panjab University, Chandigarh, India

Date of Submission15-Jul-2011
Date of Decision05-Oct-2011
Date of Acceptance28-Feb-2012
Date of Web Publication17-May-2012

Correspondence Address:
Avinash Puri
Department of Anesthesia, Post Graduate Institute of Medical Education and Research, Chandigarh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


Rights and PermissionsRights and Permissions

 » Abstract 

Objectives: To analyze population pharmacokinetics of Propofol in Indian patients after single bolus dose of Propofol using WINNONLIN program.
Materials and Methods: Population pharmacokinetics of Propofol was investigated in Indian subjects in 26 elective surgical patients (14 males and 12 females) following single bolus dose of 2 mg/kg propofol. A total of 364 samples were estimated by High Performance Liquid Chromatography and pharmacokinetic parameters were derived using WINNONLIN (5.2). The effect of demographic characters of the study population on pharmacokinetic parameters was investigated.
Results: Three-compartment model was used to describe the pharmacokinetic data of Propofol in Indian subjects. Initial volume of distribution (V1) clearance (Cl) and steady state volume of distribution (Vd ss ) was 13.5 ± 3.3 l, 1.08 ± 0.42 l/min, and 77.69 ± 48.0 l, respectively. Body weight best described the volume of central compartment (V1) as well as elimination clearance (P<0.01).
Conclusion: Pharmacokinetics of Propofol in young healthy Indian subjects show lower volume of distribution and clearance as compared with most of the western data. Body weight best describes the V1, Vd ss , and Clearance in this group.


Keywords: Anesthetics, propofol, pharmacokinetics, volume of distribution


How to cite this article:
Puri A, Medhi B, Panda NB, Puri G D, Dhawan S. Propofol pharmacokinetics in young healthy Indian subjects. Indian J Pharmacol 2012;44:402-6

How to cite this URL:
Puri A, Medhi B, Panda NB, Puri G D, Dhawan S. Propofol pharmacokinetics in young healthy Indian subjects. Indian J Pharmacol [serial online] 2012 [cited 2019 Sep 16];44:402-6. Available from: http://www.ijp-online.com/text.asp?2012/44/3/402/96348



 » Introduction Top


Propofol is an intravenous sedative hypnotic agent which is used for both induction as well as maintenance of general anesthesia. The pharmacokinetics of propofol has been evaluated extensively in the west in different patient groups after either bolus doses or continuous infusions. [1],[2],[3],[4],[5],[6],[7] And presently, there are multiple models available based on that data. [2],[3],[4] So far, the pharmacokinetics of propofol has not been studied in the Indian population. Ethnicity can be major factor in pharmacokinetics and dynamics of drugs including sedatives. [8],[9],[10],[11] With this background, we planned to evaluate pharmacokinetics of propofol in adult Indian patients which will help in better management of these patients undergoing surgery using propofol infusion in total intravenous anesthesia.


 » Materials and Methods Top


After approval from the Institutional Ethics Committee and written informed consent, 30 ASA grade 1 18 - to 55-year-old Indian patients were included. All patients underwent surgeries (laparoscopic cholecystectomy, hernioplasty, hysterectomy, septopolasty, and parotidectomy) requiring general anesthesia for less than two hours and expected blood loss of less than 10% of total blood volume. Patients with hepatitis, HIV infection, hepatic, renal, hematological, and cardiovascular diseases were excluded from the study. No pregnant patient and no patient with history of smoking or alcohol intake were included in the study. Patients were premedicated with Tab Diazepam 5 mg night before as well as 2 hours before induction. Before induction of anesthesia, two large bore intravenous lines were secured, one each in the antecubital vein and vein on dorsum of the contralateral hand. The antecubital vein was used for blood sampling. Morphine 0.12 mg/kg was injected 5 minutes before starting propofol injection. The elimination half life of morphine and morphine 3 glucuronide which is an active metabolite of morphine are 114 minutes and 173 minutes, respectively. As the cases included in this study were of less than 2-hour duration, we did not repeat morphine or give any other opioid during maintenance of anesthesia.

Injection Lignocaine 2% 1 ml was injected in the iv line followed by injection Propofol 2 mg/kg over a period of 15 seconds in the same line to induce anesthesia. Anesthesia was maintained with isoflurane, oxygen (40%) and nitrous oxide (60%), and intermittent dosages of vecuronium. Isoflurane was titrated to Bispectral index monitoring valueof 50 (Aspect medical systems Inc. Norwod, MA). On completion of surgery, inhalational anesthetics were discontinued.


 » Blood Sampling Top


Venous blood samples (3 ml) were obtained before and at 2, 4, 6, 10, 20, 30, 60, 90, 120, 240, 480, 720, and 1440 minutes after administration of propofol. Time 0 was taken as the time just before propofol administration. A total of 14 samples were collected from each patient. All samples were collected in heparinized tubes and after thorough mixing, centrifuged at 3 000 rpm for 10 minutes. The supernatant was stored at - 20°C till the time of analysis. The samples were analyzed using a modified High Performance Liquid Chromatography method described by Pavan and Buglione. [12] (Appendix 1). Pharmacokinetic analysis of each dataset was performed by using nonlinear regression program WINNONLIN (version 5.2) (Pharsight Cooperation, California). The correlation of various derived parameters with demographic data like age, weight, height, body surface area, and sex was also quantitated. Inter-group analysis was performed using the unpaired 't ' test. Pearson coefficient was calculated by using regression equation and all statistical analyses were performed using SPSS version 15.0 for Windows and a P value<0.05 was considered to be significant.


 » Results Top


Twenty-six of the 30 patients enrolled in the study completed the study uneventfully. Data of four patients were not analyzed as the sampling protocol was disturbed due to sampling line problem or unanticipated excessive blood loss.

The demographic details of the patients are shown in [Table 1].
Table 1: Demographic data (mean ± Std)

Click here to view


Propofol blood concentration declined rapidly after the bolus in all patients following which the smooth decline continued [Figure 1].
Figure 1: Plasma propofol concentration vs time in minutes

Click here to view


The blood concentration of propofol at any time after administration was best fitted for the patients in this study by a triexponential equation of the form:



Where, Cp (t) is the plasma concentration at time 't' and A, B, and C are the coefficients describing the relative contributions of each exponential term and a, b, and g are the hybrid rate constants corresponding to the rapid distribution half life, the slow distribution half life, and the elimination half life, respectively. The coefficients or intercepts in the triexponential equation describe the extent of contribution of each half life to the decay of plasma concentration following a bolus dose. [Table 2] shows fractional coefficients, such that A + B + C=100%. Initial distribution lowers the concentration by 80%, slower distribution and elimination contribute 15.2% and 4.2%, respectively. The individual constants, exponents, and the derived pharmacokinetic variables are shown in [Table 2]. Initial volume of distribution (V1) clearance (Cl) and steady state volume of distribution (Vd ss) was 13.5 ± 3.3 l, 1.08 ± 0.42 l/ min, and 77.69 ± 48.0 l, respectively, in these young healthy Indian patients.
Table 2: Pharmacokinetic parameters using single bolus dose of propofol

Click here to view


[Table 3] shows the correlation of V1 and Cl with demographic data. The coefficient of correlation between weight and V 1 and Cl was 0.842 and 0.578, respectively. Multiple regressions of these parameters with patient demographic variables showed that though weight, height, and BSA showed significant relationship with initial volume of distribution, weight best described the V 1 and Cl regression equation. Addition of other variables did not improve this relation.
Table 3: Shows the correlation of V1 and Cl with demographic data

Click here to view



 » Discussion Top


Our study describes the disposition of propofol in a group of ASA 1 adult Indian patients scheduled for elective surgical procedures.

The pharmacokinetics of propofol can be explained by the three-compartment model [Figure 2] comprising of three exponential functions
Figure 2: Phases of three compartment model

Click here to view


The three phases of the tri-exponential curve are early mixing and distribution to all tissues along with elimination. This is followed by distribution to the slowly equilibrating tissues along with drug elimination. Finally, in the terminal phase is the terminal elimination phase. The slopes of these three phases of plasma decay curve are inversely proportional to the half lives, whereas intercepts or the coefficients represent the amount that each half life contributes to the decrease in concentration following bolus dose.

The initial rapid distribution volume (V1) which contribute to 80% of plasma level disposition in all the studies has also similar half life (T 1/2 a) as shown in [Table 4]. Though the slower distribution as well as terminal elimination half lives were relatively quicker in our data, this contribute to less than 20% of the plasma level decay. The pharmacokinetic data for the patients show that the clearance was low (mean 1.08 l/ min). T1/2 g (min) was prolonged (70.9 min), indicating a high equilibrium volume of distribution estimate. The initial volume of distribution or volume of central compartment, i.e., V1 (0.214 l/kg) as well as rapidly equilibrating compartment volume, i.e., V2 (0.403 l/ kg) were comparable with that of Marsh model (0.228 l/kg and 0.463 l/kg, respectively) [2] though much lower than other western studies [Table 4]. The mean volume of distribution at steady state though large (77.7 l or 1.2 l/kg) is much lower than that of Marsh model [2] (287 l). Data suggest that after a rapid injection of single dose of propofol, the drug was rapidly cleared from the body, but a small proportion remained in tissue (presumably lipid) and was eliminated much more slowly. The elimination of propofol during the third exponential phase is constrained by its slow return from the deep to the central compartment. The elimination during the second exponential phase is probably dominated by the unconstrained metabolic clearance of propofol along with distribution to slower compartment. Compared with earlier studies, we found the third exponential phase half life to be relatively shortened (70.9 min compared with 184-674 min), whereas the half lives for the first two phases were broadly similar. [1],[2],[6],[7] This may not result in any difference in clinical recovery because of relatively smaller contribution of the same (<5%) to ultimate fall in plasma concentration.
Table 4: Comparison of pharmacokinetic parameters between different studies

Click here to view


In general, changes in the rate processes governing the clearance of an anesthetic drug from blood could result from competitive metabolism, induction or inhibition of metabolism, or an alteration of blood flow to organs playing a significant role in the clearance of the drug. Changes in distribution volume could result from change in volume of highly perfused tissues or reduced perfusion of these tissues due to low cardiac output and also due to displacement of drug from tissue binding sites. Therefore, this study was carried out in ASA 1 patients undergoing routine operations with a standardized treatment regimen. Though V1 and Cl values may show difference from other studies but the proportional contribution of A coefficient as well as the half life of this initial phase appears similar [Table 4], indicating that the routine PK variables like V1 and Cl may not give a real picture of clinical significance.

Following induction with Propofol and opioid, patients were maintained with Isoflurane. For drugs with flow-dependent clearance such as propofol, changes in hepatic blood flow can cause proportional changes in clearance. Significantly lower V1 and Cl in the present study [Table 4] as compared with earlier bolus studies [1],[6],[7] can probably be attributed to relatively lower cardiac output due to opioid administration prior to induction [13],[14],[15] as well as adequate depth of anesthesia using isoflurane and BIS monitoring.

Initial volume of distribution (V1) seemed to have no relationship with age (r=0.227) or sex (0.052) [Table 3] in the age range of patients studied (18-60 years). Similarly, no relationship was found between these patient variables and systemic clearance (Cl) (except for the r of 0.4 with Pvalue of 0.03 for its relation with age). This has been demonstrated in previous pharmacokinetic studies also. While evaluating Marsh model, White and Kenny found that the clearance and V1 of propofol in male patients changed little with age, though they found higher initial value in female patients which decreased progressively with age. Similar to our data, they also found lower propofol dosages for induction in young patients of both sexes as compared with Marsh model. [16] However, with respect to other demographic characteristics, a significant correlation existed between weight and V1 (r=0.842), height and V1 (r=0.593), and body surface area and V1 (r=0.831) (P< 0.05). Similarly, significant correlation showed in between weight and clearance (r=0.578) and body surface area and clearance (r=0.557) (P< 0.05).Unlike our and most other studies, [2,17] Kay et al. [1] did not demonstrate any significant correlation between weight (55-95 kg) and V1. This study shows that weight was found to correlate best to volume of distribution (r=0.842); the correlation constant of height with volume of distribution was found to be r=0.53. This shows that weight correlates better than height with volume of distribution, i.e., pharmacokinetics of propofol.

This study has certain limitations. To begin with, all patients were administered morphine prior to induction of anesthesia. It has been a well-known fact that the dose of propofol required to achieve a given depth of anesthesia is smaller in patients pretreated with opioids. [14] The net rate of clearance of propofol is also reduced in these patients. This may be responsible for low clearance as compared with earlier studies. Though this may contaminate the fundamental pharmacokinetic values of propofol, the clinical scenario of the present study mimics the practical situations. Hence, these derived values may have more clinical relevance and the model derived from this may be better suited to clinical situation.

We used venous samples because for research purposes, it is convenient and less traumatic, arterial puncture is avoided where possible because of increased morbidity compared with venepuncture. Major et al. [18] found that there was no significant difference between arterial, central venous, and peripheral venous concentrations of propofol at sampling time beyond one minute.

To summarize, propofol in Indian population has lower initial volume of distribution and lower clearance than most of the western studies. This may be responsible for lower propofol dosages in clinical practice. We found that weight was the only factor that significantly affects the pharmacokinetics of propofol in the 18 - to 60-year age group, though the findings of the present study may not apply to patients at the extreme ends of the spectrum. Nevertheless, these pharmacokinetic parameters need to be validated prospectively after targeting the plasma concentration. We have calculated pharmacokinetic parameters using these parameters and we will develop a pharmacokinetic model and validate our findings in further studies. This is a basic study of pharmacokinetics of propofol in Indian subjects; till now, no study has evaluated pharmacokinetics of propofol in Indian population.

Appendix 1

High Performance Liquid Chromatography method for plasma sample analysis: [12] [Table 5].
Table 5: The data for calibration graph of propofol concentration vs HPLC area

Click here to view


Plasma samples were analyzed using a modified High Performance Liquid Chromatography

(HPLC) method described by Pavan and Buglione. [12]

67 ml of acetonitrile was mixed with 33 ml of perchloric acid to make 100 ml of solution. Solution of dibutyl phthalate of 200 μL was mixed with the 100 ml of above mixed solution. 500 μl of above solution was mixed with 500 μl of plasma and this solution was vortexed for 10 minutes and then centrifuged at 10 000 rpm for 10 minutes, after centrifugation, 20 μl supernatant was collected for injection into column.

Linearity was validated by measuring area responses at the concentration range of 0.001 to 12 μg/ml. Two separate stock solutions were prepared, the same serial dilutions were made, and each sample was injected in duplicate. A linear regression analysis was performed.

The calibration curve was found to be linear in the range 0.001 to 12 ug/ml [Figure 3].
Figure 3: Calibration curve of propofol against different known concentration

Click here to view


And, the equation was (y=438.7x + 20.44)

Y=Area

X=concentration

R 2 =0.999

The minimum detectable concentration of the analyte (is the smallest concentration that can be detected reliably) and the Limit of detection is related to both the signal and the noise of the system as usually is defined as whose signal to noise ratio S/N ratio is at least 3 to 1. The minimum quantifiable amount often known as the limit of quantification is the concentration that can be quantitated reliably with specific level of accuracy and precision. The limit of detection was found to be 0.0001 μg/ml while limit of quantification was found to be 0.001 μg/ml as evident from the calibration curve.

HPLC variables used in this method

Column: 250 × 4.6 10 um Spherisorb C 18

Mobile phase: MeCN: water: acetic acid 67:33:0.04, pH 4.0

Flow rate-1.5 ml/min

Injection volume-20 μl

Retention time-13 minutes

Detector: UV 270 nanometer

CHROMATOGRAM:

Limit of detection: 0.0001 μg/ml

Internal standard: dibutyl phthalate

External standard: propofol

 
 » References Top

1.Kay NH, Sear JW, Uppington J, Cockshott ID, Douglas EJ. Disposition of propofol in patients undergoing surgery. Br J Anaesth 1986;58:1075-9.  Back to cited text no. 1
[PUBMED]  [FULLTEXT]  
2.Gepts E, Camu F, Cockshott I, Douglas E. Disposition of Propofol administered as constant rate intravenous infusions in humans. Anesth Analg 1987;66:1256-63.  Back to cited text no. 2
    
3.Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 1991;67:41-8.  Back to cited text no. 3
[PUBMED]  [FULLTEXT]  
4.Schnider TW, Minto CF, Gambus PL, Andresen C, Goodale DB, Shafer SL, et al. The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology 1998;88:1170-82.  Back to cited text no. 4
[PUBMED]  [FULLTEXT]  
5.White M, Kenny GN. Intravenous propofol anesthesia using a computerized infusion system. Anaesthesia 1990;45:204-9.  Back to cited text no. 5
[PUBMED]    
6.Kirkpatrick T, Cockshott ID, Douglas EJ, Nimmo WS. Pharmacokinetics of propofol (Diprivan) in elderly patients. Br J Anaesth 1988;60:146-50.  Back to cited text no. 6
[PUBMED]  [FULLTEXT]  
7.Cockshott ID, Briggs LP, Douglas EJ, White M. Pharmacokinetics of Propofol in female patients. Br J Anaesth 1987;59:1103-10.  Back to cited text no. 7
[PUBMED]  [FULLTEXT]  
8.Johnsons JA. Predictability of the effects of race or ethnicity on Pharmacokinetics of drugs. Int J Clin Pharmacol Ther 2000;38:53-60.  Back to cited text no. 8
    
9.Xie HG, Kim RB, Wood AJ, Stein CM. Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol 200141:815-50.  Back to cited text no. 9
    
10.Ortolani O, Conti A, Chan YK, Sie MY, Ong GS. Comparison of propofol consumption and recovery time in Caucasians from Italy, with Chinese, Malays and Indians from Malaysia. Anaesth Intensive Care 2004;32:250-5.  Back to cited text no. 10
[PUBMED]    
11.Chen ML. Ethnic or racial differences revisited: Impact of dosage regimen and dosage form on pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2006;45:957-64.  Back to cited text no. 11
[PUBMED]  [FULLTEXT]  
12.Pavan I, Buglione E. Monitoring propofol serum levels by rapid and sensitive reversed phase high performance liquid chromatography during prolonged sedation in ICU patients. J Chromatogr Sci 1992;30:164-6.  Back to cited text no. 12
    
13.Hoymork SC, Raeder J, Grimsmo B, Steen PA. Bispectral Index, Predicted and measured drug levels of target controlled infusions of remifenatnil and propofol during laparoscopic cholecystectomy and emergence. Acta Anaesthesiol Scand 2000:44:1138-44.  Back to cited text no. 13
    
14.Barvais L, Rausin I, Glen JB, Hunter SC, D'Hulster D, Cantraine F, et al. Administration of propofol by target-controlled infusion in patients undergoing coronary artery surgery. J Cardiothorac Vasc Anesth 1996;10:877-83.  Back to cited text no. 14
[PUBMED]    
15.Prys Roberts C. Influence of the induction scheme on the hemodynamic effect of Propofol. In: Proceedings of the 9 th World Congress Anesthesiology, Washington; 1988.  Back to cited text no. 15
    
16.White M, Kenny GC. Use of target controlled infusion to derive age and gender covariates for propofol clearance. Clin Pharmacokinet 2008;47:119-22.  Back to cited text no. 16
    
17.Li HY, Zhong-Jian RU, Gang ZY, Wang LQ, Fu SE, Yang JJ, et al. Population pharmacokinetics of propofol in Chinese patients. Acta Pharmacol Sin 2003;24:581-8.  Back to cited text no. 17
    
18.Major E, Aun C, Yate PM, Savege TM, Verniquet AJW, Adam H, et al. Influence of sample site on blodd concentrations of ICI 35868. Br J Anaesth 1983;55:371-5.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

This article has been cited by
1 Gender-Specific Differences in the Central Nervous Systemęs Response to Anesthesia
Mawhinney, L.J., Mabourakh, D., Lewis, M.C.
Translational Stroke Research. 2013; 4(4): 462-475
[Pubmed]
2 Three-bottle exponential decay infusion: A novel intravenous infusion strategy for drugs which conform to three-compartment model with observations on propofol kinetics
Huang, X.-h., Xie, H.-t., Wang, K., Huang, J.-h., Sun, R.-y.
Bangladesh Journal of Pharmacology. 2012; 7(4): 223-235
[Pubmed]



 

Top
Print this article  Email this article
 

    

Site Map | Home | Contact Us | Feedback | Copyright and Disclaimer
Online since 20th July '04
Published by Wolters Kluwer - Medknow