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Pharmaceutical Research

, Volume 30, Issue 9, pp 2368–2384 | Cite as

Brain Disposition and Catalepsy After Intranasal Delivery of Loxapine: Role of Metabolism in PK/PD of Intranasal CNS Drugs

  • Yin Cheong Wong
  • Zhong Zuo
Research Paper

ABSTRACT

Purpose

To elucidate the role of metabolism in the pharmacokinetics and pharmacodynamics of intranasal loxapine in conscious animals.

Methods

At pre-determined time points after intranasal or oral loxapine administration, levels of loxapine, loxapine metabolites, and neurotransmitters in rat brain were quantified after catalepsy assessments (block test and paw test). Cataleptogenicity of loxapine was also compared with its metabolites.

Results

Intranasally administered loxapine was efficiently absorbed into systemic circulation followed by entering brain, with tmax ≤15 min in all brain regions. Oral route delivered minimal amounts of loxapine to plasma and brain. Brain AUC0–240min values of 7-hydroxy-loxapine were similar after intranasal and oral administration. Intranasal loxapine tended to induce less catalepsy than oral loxapine, although statistical significance was not reached. The catalepsy score was positively and significantly correlated with the striatal concentration of 7-hydroxy-loxapine, but not with loxapine. 7-hydroxy-loxapine was more cataleptogenic than loxapine, while the presence of loxapine tended to reduce rather than intensify 7-hydroxy-loxapine-induced catalepsy. The increases in striatal dopamine turnover were comparable after intranasal and oral loxapine administration.

Conclusions

The metabolite 7-hydroxy-loxapine, but not loxapine, was the main contributor to the catalepsy observed after intranasal and oral loxapine treatment. Intranasal route could effectively deliver loxapine to brain.

KEY WORDS

antipsychotics catalepsy central nervous system intranasal administration metabolism 

ABBREVIATIONS

3-MT

3-methoxytyramine

5-HIAA

5-hydroxyindole-3-acetic acid

5-HT

Serotonin

7-OH-amoxapine

7-hydroxy-amoxapine

7-OH-loxapine

7-hydroxy-loxapine

8-OH-amoxapine

8-hydroxy-amoxapine

8-OH-loxapine

8-hydroxy-loxapine

AUC

area under the curve

Cmax

maximum concentration

CNS

central nervous system

CYP

cytochrome P450

DA

dopamine

DOPAC

3,4-dihydroxyphenylacetic acid

HVA

homovanillic acid

IM

intramuscular

IV

intravenous

PD

pharmacodynamics

PK

pharmacokinetics

t1/2

half life

tmax

time to maximum concentration

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

CUHK Direct Grant 4450272 and General Research Fund CUHK 480809.

Supplementary material

11095_2013_1080_MOESM1_ESM.docx (379 kb)
ESM 1 (DOCX 379 kb)

REFERENCES

  1. 1.
    Wong YC, Zuo Z. Intranasal delivery–modification of drug metabolism and brain disposition. Pharm Res. 2010;27(7):1208–23.Google Scholar
  2. 2.
    Wong YC, Qian S, Zuo Z. Regioselective biotransformation of CNS drugs and its clinical impact on adverse drug reactions. Expert Opin Drug Metab Toxicol. 2012;8(7):833–54.PubMedCrossRefGoogle Scholar
  3. 3.
    Midha KK, Hubbard JW, McKay G, Hawes EM, Hsia D. The role of metabolites in a bioequivalence study 1: loxapine, 7-hydroxyloxapine and 8-hydroxyloxapine. Int J Clin Pharmacol Ther Toxicol. 1993;31(4):177–83.PubMedGoogle Scholar
  4. 4.
    Wong YC, Wo SK, Zuo Z. Investigation of the disposition of loxapine, amoxapine and their hydroxylated metabolites in different brain regions, CSF and plasma of rat by LC–MS/MS. J Pharm Biomed Anal. 2012;58(1):83–93.Google Scholar
  5. 5.
    Richelson E. Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry. 1999;60 Suppl 10:5–14.PubMedGoogle Scholar
  6. 6.
    Pierre JM. Extrapyramidal symptoms with atypical antipsychotics: incidence, prevention and management. Drug Saf. 2005;28(3):191–208.PubMedCrossRefGoogle Scholar
  7. 7.
    Porsolt RD, Moser PC, Castagné V. Behavioral indices in antipsychotic drug discovery. J Pharmacol Exp Ther. 2010;333(3):632–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Hoffman DC, Donovan H. Catalepsy as a rodent model for detecting antipsychotic drugs with extrapyramidal side effect liability. Psychopharmacology (Berl). 1995;120(2):128–33.CrossRefGoogle Scholar
  9. 9.
    Wadenberg MLG, Kapur S, Soliman A, Jones C, Vaccarino F. Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behaviour in rats. Psychopharmacology (Berl). 2000;150(4):422–9.CrossRefGoogle Scholar
  10. 10.
    Kumar M, Misra A, Babbar AK, Mishra AK, Mishra P, Pathak K. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm. 2008;358(1–2):285–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Kumar M, Misra A, Mishra AK, Mishra P, Pathak K. Mucoadhesive nanoemulsion-based intranasal drug delivery system of olanzapine for brain targeting. J Drug Target. 2008;16(10):806–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Patel S, Chavhan S, Soni H, Babbar AK, Mathur R, Mishra AK, et al. Brain targeting of risperidone-loaded solid lipid nanoparticles by intranasal route. J Drug Target. 2011;19(6):468–74.PubMedCrossRefGoogle Scholar
  13. 13.
    Illum L. Nasal delivery. The use of animal models to predict performance in man. J Drug Target. 1996;3(6):427–42.PubMedCrossRefGoogle Scholar
  14. 14.
    Hirai S, Yashiki T, Matsuzawa T, Mima H. Absorption of drugs from the nasal mucosa of rat. Int J Pharm. 1981;7(4):317–25.CrossRefGoogle Scholar
  15. 15.
    Mayor SH, Illum L. Investigation of the effect of anaesthesia on nasal absorption of insulin in rats. Int J Pharm. 1997;149(1):123–9.CrossRefGoogle Scholar
  16. 16.
    Yang Z, Huang Y, Gan G, Sawchuk RJ. Microdialysis evaluation of the brain distribution of stavudine following intranasal and intravenous administration to rats. J Pharm Sci. 2005;94(7):1577–88.PubMedCrossRefGoogle Scholar
  17. 17.
    Sanberg PR, Martinez R, Shytle RD, Cahill DW. The catalepsy test: is a standardized method possible? In: Sanberg PR, Ossenkopp KP, Kavaliers M, editors. Motor activity and movement disorders Totowa. NJ: Humana Press; 1996. p. 197–211.CrossRefGoogle Scholar
  18. 18.
    Sanberg PR, Bunsey MD, Giordano M, Norman AB. The catalepsy test: its ups and downs. Behav Neurosci. 1988;102(5):748–59.PubMedCrossRefGoogle Scholar
  19. 19.
    Vrijmoed-De Vries MC, Tonissen H, Cools AR. The relationship between hindlimb disturbances, forelimb disturbances and catelepsy after increasing doses of muscimol injected into the striatal-pallidal complex. Psychopharmacology (Berl). 1987;92(1):73–7.CrossRefGoogle Scholar
  20. 20.
    Ellenbroek BA, Peeters BW, Honig WM, Cools AR. The paw test: a behavioral paradigm for differentiating between classical and atypical neuroleptic drugs. Psychopharmacology (Berl). 1987;93(3):343–8.CrossRefGoogle Scholar
  21. 21.
    Costall B, Naylor RJ. Neuroleptic and non neuroleptic catalepsy. Arzneimittelforschung. 1973;23:674–83.PubMedGoogle Scholar
  22. 22.
    Stille G, Lauener H. Pharmacology of catatonigenic substances. 1. Correlation between neuroleptic catalepsy and the homovanillic acid level in rat corpus striatum. Arzneimittelforschung. 1971;21(2):252–5.Google Scholar
  23. 23.
    Tareke E, Bowyer JF, Doerge DR. Quantification of rat brain neurotransmitters and metabolites using liquid chromatography/electrospray tandem mass spectrometry and comparison with liquid chromatography/electrochemical detection. Rapid Commun Mass Spectrom. 2007;21(23):3898–904.PubMedCrossRefGoogle Scholar
  24. 24.
    Diop L, Gottberg E, Briere R, Grondin L, Reader TA. Distribution of dopamine D1 receptors in rat cortical areas, neostriatum, olfactory bulb and hippocampus in relation to endogenous dopamine contents. Synapse. 1988;2(4):395–405.Google Scholar
  25. 25.
    Ereshefsky L. Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic. J Clin Psychiatry. 1999;60 Suppl 10:20–30.PubMedGoogle Scholar
  26. 26.
    Narige T, Mizumura M, Okuizumi N, Matsumoto K, Furukawa Y, Hondo T. Study of the absorption, distribution, metabolism, and excretion of amoxapine in rats. Yakuri to Chiryo. 1981;9(5):1885–92.Google Scholar
  27. 27.
    Furubayashi T, Kamaguchi A, Kawaharada K, Masaoka Y, Kataoka M, Yamashita S, et al. Evaluation of the contribution of the nasal cavity and gastrointestinal tract to drug absorption following nasal application to rats. Biol Pharm Bull. 2007;30(3):608–11.PubMedCrossRefGoogle Scholar
  28. 28.
    Tuk B, Van Oostenbruggen MF, Herben VMM, Mandema JW, Danhof M. Characterization of the pharmacodynamic interaction between parent drug and active metabolite in vivo: midazolam and alpha-OH-midazolam. J Pharmacol Exp Ther. 1999;289(2):1067–74.Google Scholar
  29. 29.
    Burstein S, Hunter SA, Latham V, Renzulli L. A major metabolite of Δ1-tetrahydrocannabinol reduces its cataleptic effect in mice. Experientia. 1987;43(4):402–3.PubMedCrossRefGoogle Scholar
  30. 30.
    Bun SS, Voeurng V, Bun H. Interspecies variability and drug interactions of loxapine metabolism in liver microsomes. Eur J Drug Metab Pharmacokinet. 2003;28(4):295–300.PubMedCrossRefGoogle Scholar
  31. 31.
    Burki HR, Fischer R, Hunziker F. Dibenzo-epines: effect of the basic side-chain on neuroleptic activity. Eur J Med Chem. 1978;13(5):479–85.Google Scholar
  32. 32.
    Seeman P. Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Targets. 2006;10(4):515–31.PubMedCrossRefGoogle Scholar
  33. 33.
    Midha KK, Rawson MJ, Hubbard JW. The role of metabolites in bioequivalence. Pharm Res. 2004;21(8):1331–44.PubMedCrossRefGoogle Scholar
  34. 34.
    Paprocki J, Versiani M. A double-blind comparison between loxapine and haloperidol by parenteral route in acute schizophrenia. Curr Ther Res Clin Exp. 1977;21(1):80–100.PubMedGoogle Scholar
  35. 35.
    Simpson GM, Cooper TB, Lee JH, Young MA. Clinical and plasma level characteristics of intramuscular and oral loxapine. Psychopharmacology (Berl). 1978;56(2):225–32.CrossRefGoogle Scholar
  36. 36.
    Al-Suwayeh SA, Tebbett IR, Wielbo D, Brazeau GA. In vitro-in vivo myotoxicity of intramuscular liposomal formulations. Pharm Res. 1996;13(9):1384–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Chakrabarti A, Bagnall A, Chue P, Fenton M, Palaniswamy V, Wong W, et al. Loxapine for schizophrenia. Cochrane Database Syst Rev. 2007;4, CD001943.PubMedGoogle Scholar
  38. 38.
    Sztrymf B, Chevrel G, Bertrand F, Margetis D, Hurel D, Ricard J, et al. Beneficial effects of loxapine on agitation and breathing patterns during weaning from mechanical ventilation. Crit Care. 2010;14(3).Google Scholar
  39. 39.
    Krieger D, Hansen K, McDermott C, Matthews R, Mitchell R, Bollegala N, et al. Loxapine versus olanzapine in the treatment of delirium following traumatic brain injury. NeuroRehabilitation. 2003;18(3):205–8.PubMedGoogle Scholar
  40. 40.
    Reinblatt SP, Abanilla PK, Jummani R, Coffey B. Loxapine treatment in an autistic child with aggressive behavior: therapeutic challenges. J Child Adolesc Psychopharmacol. 2006;16(5):639–43.PubMedCrossRefGoogle Scholar
  41. 41.
    Carlyle W, Ancill RJ, Sheldon L. Aggression in the demented patient: a double-blind study of loxapine versus haloperidol. Int Clin Psychopharmacol. 1993;8(2):103–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Hale RL, Munzar P, Rabinowitz JD, inventors. Alexza Molecular Delivery Corporation, USA, assignee. Method for treating pain with loxapine and amoxapine. Patent Application Country: Application: US; Patent Country: US; Priority Application Country: US patent 2004102434. 2004 0527; Patent Application Date: 20031120.; Priority Application Date: 20021126.Google Scholar
  43. 43.
    Kimishima K, Sakamoto T, Yamasaki M, Tanabe K, Amano Y. Central nervous actions of new neuroleptics, dibenzoazepine derivatives. Yonago Igaku Zasshi. 1969;20(6):525–36.Google Scholar
  44. 44.
    Stefanova D. Cloxazepine—neuropharmacological studies. Eksp Med Morfol. 1981;20(4):208–13.PubMedGoogle Scholar
  45. 45.
    Chen YW, Huang KL, Liu SY, Tzeng JI, Chu KS, Lin MT, et al. Intrathecal tri-cyclic antidepressants produce spinal anesthesia. Pain. 2004;112(1–2):106–12.PubMedCrossRefGoogle Scholar
  46. 46.
    Matsudaira K, Seichi A, Yamazaki T, Kishimoto J, Takeshita K, Nakamura K. Efficacy of tricyclic antidepressant for somatoform pain disorders with chronic lower back and leg pain. J Lumbar Spine Disord. 2004;10(1):155–62.CrossRefGoogle Scholar
  47. 47.
    Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):614–28.PubMedCrossRefGoogle Scholar
  48. 48.
    Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci. 2011;12(10):570–84.PubMedCrossRefGoogle Scholar
  49. 49.
    Johnson NJ, Hanson LR, Frey II WH. Trigeminal pathways deliver a low molecular weight drug from the nose to the brain and orofacial structures. Mol Pharm. 2010;7(3):884–93.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.School of Pharmacy, Faculty of MedicineThe Chinese University of Hong KongShatinHong Kong

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