Pharmaceutical Research

, Volume 19, Issue 6, pp 858–867 | Cite as

Sex Specificity in Methadone Analgesia in the Rat: A Population Pharmacokinetic and Pharmacodynamic Approach

  • Monica Rodriguez
  • M. Angeles Carlos
  • Ignacio Ortega
  • Elena Suarez
  • Rosario Calvo
  • John C. Lukas
Article

Abstract

Purpose. To quantify the extent to which a sex-specific dichotomy in the temporal evolution of the analgesic effect, after intravenous (i.v.) methadone injection in the rat, relates to the pharmacokinetics (PK) and pharmacodynamics (PD) that mediate the dose-to-effect pathway.

Methods. Tail-flick analgesia was measured after i.v. methadone injection (0.35 mg/kg) in female (n = 16) and male (n = 16) Sprague-Dawley rats. The PK were evaluated in separate female (n = 56) and male (n = 56) rats after they had received the same dose of methadone i.v. (0.35 mg/kg). A bicompartmental model described the kinetics and a sigmoid Emax model-related drug effect vs. simulated concentrations (pharmacodynamics) at the times of effect measurement. All model parameters as well as interanimal and assay variabilities were estimated with a mixed-effects population method using the program NONMEM.

Results. The area under the effect-time curve (AUCE0-120) was (mean ± interanimal SD) 1859 ± 346 min in the females, which was significantly lower than the 4871 ± 393 min in the males (P < 0.0001). On the contrary, the profiles of concentration vs. time were higher in females and, therefore, corresponded inversely to the effect vs. time-relative magnitudes. The central volume of distribution, V1, was 1.94 ± 0.37 l/kg for female rats and 3.01 ± 0.33 l/kg for male rats. Also, the central clearance was 0.077 ± 0.006 l/min/kg and 0.102 ± 0.005 l/min/kg, respectively, for female and male rats. Both parameters differed significantly between sexes (P < 0.0001). The pharmacodynamic maximum observed effect parameter (Emax) was 37% ± 29% in female rats and 85% ± 16% in male rats, and these values were significantly different (P < 0.0001). The parameter for the concentration eliciting half of Emax (EC50) was 24.1 ± 7.5 μg/l in female rats and 20.3 ± 2.9 μg/l in male rats, and the Hill-related exponent, γ, was 6.3 ± 3.9 in female rats and 5.5 ± 4.1 in male rats. These parameters did not differ significantly (at the P < 0.05 level).

Conclusions. A sex-specific dichotomy in the methadone antinociceptive effect, in the rat, was not proportionally related to plasma concentrations. Each sex corresponded to a distinct subpopulation of the PK parameters and one of the pharmacodynamic parameters (Emax). When the course of a drug involves PK or PD subpopulations, PK/PD modeling can afford the safest prediction of the effect-time evolution for a particular dose.

sex difference pharmacokinetics pharmacodynamics nonlinear mixed effects NONMEM population 

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REFERENCES

  1. 1.
    A. I. Baamonde, A. Hidelgo, and F. Andres-Trelles. Sex related differences in the effects of morphine and stress on visceral pain. Neuropharmacology 28:967–970 (1989).Google Scholar
  2. 2.
    T. J. Cicero, B. Nock, and E. R. Meyer. Gender-related differences in the antinociceptive properties of morphine. J. Pharmacol. Exp. Ther. 279:767–773 (1996).Google Scholar
  3. 3.
    T. J. Cicero, B. Nock, and E. R. Meyer. Sex-related differences in morphine´ s antinociceptive activity: Relationship to serum and brain morphine concentration. J. Pharmacol. Exp. Ther. 282:939–944 (1997).Google Scholar
  4. 4.
    B. Kest, E. Sarton, and A. Dahan. Gender differences in opioidmediated analgesia. Anesthesiology 93:539–547 (2000).Google Scholar
  5. 5.
    R. Z. Harris, L. Z. Benet, and J. B. Schwartz. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 50:222–239 (1995).Google Scholar
  6. 6.
    P. A. Thurmann and B. C. Hompesch. Influence of gender on the pharmacokinetics and pharmacodynamics of drugs. Int. J. Clin. Pharmacol. Ther. 36:586–590 (1998).Google Scholar
  7. 7.
    B. Beierle. Meibohm, and H. Derendorf. Gender differences in pharmacokinetics and pharmacodynamics. Int. J. Clin. Pharmacol. Ther. 37:529–547 (1999).Google Scholar
  8. 8.
    P. L. Bonate. Gender-related differences in xenobiotic metabolism. J. Clin. Pharmacol. 31:684–690 (1991).Google Scholar
  9. 9.
    R. Kato and Y. Yamazoe. Sex-specific cytochrome P-450 as a cause of sex-and species-related differences in drug toxicity. Toxicol. Lett. 65:661–667 (1992).Google Scholar
  10. 10.
    E. Tanaka. Gender-related differences in pharmacokinetics and their clinical significance. J. Clin. Pharmacol. Ther. 24:339–346 (1999).Google Scholar
  11. 11.
    P. A. Routledge, W. W. Stargel, B. B. Kitchell, A. Barchowsky, and D. G. Shand. Sex-related differences in the plasma protein binding of lignocaine and diazepam. Br. J. Clin. Pharmacol. 11:245–250 (1981).Google Scholar
  12. 12.
    M. Farrell, J. Ward, R. Mattick, W. Hall, G. V. Stimson, D. des Jarlais, M. Gossop, and J. Strang. Methadone maintenance treatment in opiate dependence: A review. Br. Med. J. 309:997–1001 (1994).Google Scholar
  13. 13.
    R. Fainsinger, T. Schoeller, and E. Bruera. Methadone in the management of cancer pain: a review. Pain 52:137–147 (1993).Google Scholar
  14. 14.
    C. Ripamonti, E. Zecca, and E. Bruera. An update on the clinical use of methadone for cancer pain. Pain 70:109–115 (1997).Google Scholar
  15. 15.
    K. R. Dyer, D. J. Foster, J. M. White, A. A. Somogyi, A. Menelaou, and F. Bochner. Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration-effect relationships. Clin. Pharmacol. Ther. 65:685–694 (1999).Google Scholar
  16. 16.
    C. E. Inturrisi, W. A. Colburn, R. F. Kaiko, R. W. Houden, and K. M. Foley. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin. Pharmacol. Ther. 41:392–401 (1987).Google Scholar
  17. 17.
    K. Wolff, A. Rostami-Hodjegan, S. Shires, A. W. M. Hay, M. Feely, R. Calvert, D. Raistrick, and G. T. Tucker. The pharmacokinetics of methadone in healthy subjects and opiate users. Br. J. Clin. Pharmacol. 44:325–334 (1997).Google Scholar
  18. 18.
    C. B. Eap, C. Cuendet, and P. Baumann. Binding of dmethadone, l-methadone and d-l-methadone to protein in plasma of healthy volunteers: Role of the variants of a1-acid glycoprotein. Clin. Pharmacol. Ther. 47:338–346 (1990).Google Scholar
  19. 19.
    E. Gomez, R. Martinez-Jorda, E. Suarez, M. J. Garrido, and R. Calvo. Altered methadone analgesia due to changes in plasma protein binding: Role of the route of administration. Gen. Pharmacol. 26:1273–1276 (1995).Google Scholar
  20. 20.
    D. Rostami-Hodjegan, W. Wolff, A. W. M. Hay, D. Raistrick, R. Calvert, and G. T. Tucker. Population pharmacokinetics of methadone in opiate users: Characterization of time-dependent changes. Br. J. Clin. Pharmacol. 48:43–52 (1999).Google Scholar
  21. 21.
    D. J. Foster, A. A. Somogyi, and F. Bochner. Methadone Ndemethylaction in human liver microsomes: Lack of stereoselectivity and involvement of CYP3A4. Br. J. Clin. Pharmacol. 47:403–412 (1999).Google Scholar
  22. 22.
    R. K. Verbeeck. J-A Cardinal, and S. M. Wallace. Effect of age and gender on the plasma binding of acidic and basic drugs. Eur. J. Clin. Pharmacol. 27:91–97 (1984).Google Scholar
  23. 23.
    R. E. Bartok and R. M. Craft. Sex differences in opioid antinociception. J. Pharmacol. Exp. Ther. 282:769–778 (1997).Google Scholar
  24. 24.
    J. Candido, K. Lutfy, B. Billings, V. Sierra, A. Duttaroy, C. E. Inturrisi, and B. C. Yoburn. Effect of adrenal and sex hormones on opioid analgesia and opioid receptor regulation. Pharmacol. Biochem. Behav. 42:685–692 (1992).Google Scholar
  25. 25.
    F. E. D'Amour and D. L. Smith. A method for determining loss of pain sensation. J. Pharmacol. Exp. Ther. 72:74–79 (1941).Google Scholar
  26. 26.
    K. Wolff, M. Sanderson, A. W. M. Hay, and D. Raistrick. Methadone concentrations in plasma and their relationship to drug dosage. Clin. Chem. 37:205–209 (1991).Google Scholar
  27. 27.
    M. J. Garrido, M. Valle, R. Calvo, and I. F. Troconiz. Altered plasma and brain disposition and pharmacodynamics of methadone in abstinent rats. J. Pharmacol. Exp. Ther. 288:179–187 (1999).Google Scholar
  28. 28.
    E. I. Ette, A. W. Kelman, C. A. Howie, and B. Whiting. Analysis of animal pharmacokinetic data: performance of the one point per animal design. J. Pharmacokinet. Biopharm. 23:551–566 (1995).Google Scholar
  29. 29.
    L. B. Sheiner, D. R. Stanski, S. Vozeh, R. D. Miller, and J. Ham. Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine. Clin. Pharmacol. Ther. 25:358–371 (1979).Google Scholar
  30. 30.
    A. M. Davis and C. E. Inturrisi. d-Methadone blocks morphine tolerance and N-methyl-d-aspartate induced hyperalgesia. J. Pharmacol Exp. Ther. 289:1048–1053 (1999).Google Scholar
  31. 31.
    K. L. Kepler, K. M. Standifer, D. Paul, G. W. Pasternak, B. Kest, and R. J. Bodnar. Gender effects upon central opioid analgesia. Pain 45:87–94 (1991).Google Scholar
  32. 32.
    R. M. Craft, J. A. Stratmann, R. E. Bartok, T. I. Walpole, and S. J. King. Sex differences in development of morphine tolerance and dependence in the rat. Psychopharmacology 143:1–7 (1999).Google Scholar
  33. 33.
    K. Wolff, A. Rostami-Hodjegan, A. W. M. Hay, D. Raistrick, and G. Tucker. Population based pharmacokinetic approach for methadone monitoring of opiate addicts: Potential clinical utility. Addiction 95:1771–1783 (2000).Google Scholar
  34. 34.
    G. S. F. Ling, J. C. Umans, and C. E. Inturrisi. Methadone: Radioimmunoassay and pharmacokinetics in the rat. J. Pharmacol. Exp. Ther. 217:147–151 (1981).Google Scholar
  35. 35.
    M.-I. Nilsson, E. Anggard, and J. Holmstrand. and L-M Gunne. Pharmacokinetics of methadone during maintenance treatment: Adaptive changes during the induction phase. Eur. J. Clin. Pharmacol. 22:343–349 (1982).Google Scholar
  36. 36.
    K. Wilson, C. N. Reynolds, and D. Burnett. Inter and intraindividual variation in the metabolism of methaqualone in man after a single oral dose. Eur. J. Clin. Pharmacol. 13:291–297 (1978).Google Scholar
  37. 37.
    J. D. Lane, J. F. Steege, S. L. Rupp, and C. M. Kuhn. Menstrual cycle effects on caffeine elimination in the human female. Eur. J. Clin. Pharmacol. 43:543–546 (1992).Google Scholar
  38. 38.
    M. Rowland and T. N. Tozer. Clinical Pharmacokinetics: Concepts and Applications 3rd Ed. William & Wilkins, Media, PA, 1995 pp. 137–155.Google Scholar
  39. 39.
    D. J. Greenblat, H. Friedman, E. S. Burstein, J. M. Scavone, G. T. Blyden, H. R. Ochs, L. G. Miller, J. S. Harmatz, and R. I. Shader. Trazodone kinetics: Effect of age, gender, and obesity. Clin. Pharmacol. Ther. 42:193–200 (1987).Google Scholar
  40. 40.
    E. Schwartz, R. S. Matteo, E. Ornstein, W. L. Young, and K. L. Myers. Pharmacokinetics of sufentanil in obese patients. Anesth. Analg. 73:790–793 (1991).Google Scholar
  41. 41.
    C. M. Hunt, W. R. Westerkam, and G. M. Stave. Effect of age and gender on the activity of human hepatic CYP3A. Biochem. Pharmacol. 44:275–283 (1992).Google Scholar
  42. 42.
    E. K. Krzanowska and R. J. Bodner. Morphine antinociception elicited from the ventrolateral periaductal gray is sensitive to sex and gonadectomy differences in rats. Brain Res. 821:224–230 (1999).Google Scholar
  43. 43.
    J. S. Boyer, M. M. Morgan, and R. M. Craft. Microinjection of morphine into rostral ventromedial medulla produces greater antinociception in male compared to female rats. Brain Res. 796:315–318 (1998).Google Scholar
  44. 44.
    S. J. Liu, D. L. Roerig, and R. I. H. Wang. Brain and plasma levels of methadone and their relationship to analgesic activity of methadone in rats. Drug Metab. Dispos. 11:335–338 (1983).Google Scholar
  45. 45.
    K. Kristensen, C. B. Christensen, and L. L. Christrup. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci. 56:45–50 (1995).Google Scholar
  46. 46.
    K. Kristensen, T. Blemmer, H. R. Angelo, L. L. Christrup, N. E. Drenck, S. M. Rasmussen, and P. Sjogren. Stereoselective pharmacokinetics of methadone in chronic pain patients. Ther. Drug Monitor. 18:221–227 (1996).Google Scholar
  47. 47.
    M. A. Carlos, P. du Souich, R. Carlos, E. Suarez, J. C. Lukas, and R. Calvo. Effect of omeprazole on oral and intravenous RS-methadone pharmacokinetics and pharmacodynamics in the rat. J. Pharm. Sci. 91:1627–1638 (2002).Google Scholar
  48. 48.
    C. Cordon-Cardo, J. P. O'Brien, D. Casals, L. Rittman-Grauer, J. L. Bierdler, M. R. Melamed, and J. R. Bertino. Multidrug resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA 86:695–698 (1989).Google Scholar
  49. 49.
    R. Bouer, L. Barthe, C. Philibert, C. Tourmaire, J. Woodley, and G. Houin. The roles of P-glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat-inverted intestinal sack. Fundam. Clin. Pharmacol. 13:494–500 (1999).Google Scholar
  50. 50.
    S. J. Thopmson, D. V. M. Kari Koszdin, and C. M. Bernards. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 92:1392–1399 (2000).Google Scholar
  51. 51.
    C. J. R. Parker, J. M. Hunter, and S. L. Snowdon. Effect of age, gender, and anesthetic technique on the pharmacodynamics of atracurium. Br. J. Anaesth. 70:38–41 (1993).Google Scholar
  52. 52.
    E. Sarton, E. Olofsen, R. Romberg, J. Hartigh, B. Kest, D. Nieuwenhuijs, A. Burm, L. Teppema, and A. Dahan. Sex differences in morphine analgesia. Anesthesiology 93:1245–1254 (2000).Google Scholar
  53. 53.
    R. P. Hammer. Mu-opiate receptor binding in the medial preoptic area is cyclical and sexually dimorphic. Brain Res. 515:187–192 (1990).Google Scholar
  54. 54.
    R. B. Simerly, L. Swanson, and R. A. Gorski. Demonstration of a sexual dimorphism in the distribution of serotonin inmunoreactive fevers in the medial preoptic nucleus of the rat. J. Comp. Neurol. 225:151–176 (1984).Google Scholar
  55. 55.
    K. L. Kepler, B. Kest, J. M. Kiefel, M. L. Cooper, and R. J. Bodnar. Roles of gender and gonadectomy and estrous phase in the analgesic effects of intracerebroventricular morphine in rats. Pharmacol. Biochem. Behav. 34:119–127 (1989).Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Monica Rodriguez
    • 1
  • M. Angeles Carlos
    • 1
  • Ignacio Ortega
    • 1
  • Elena Suarez
    • 1
  • Rosario Calvo
    • 1
    • 2
  • John C. Lukas
    • 1
  1. 1.Department of Pharmacology, Faculty of MedicineUniversity of the Basque CountryLeioa, VizcayaSpain
  2. 2.Department of Pharmacy, School of PharmacyUniversity of WashingtonSeattle

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