Download PDF
Drug Res (Stuttg) 2018; 68(01): 54-59
DOI: 10.1055/s-0043-117775
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Saliva versus Plasma Bioequivalence of Valsartan/Hydrochlorothiazide in Humans: Validation of Classes II and IV Drugs of the Salivary Excretion Classification System

Nasir Idkaidek
1   University of Petra, College of Pharmacy, Amman, Jordan
,
Haneen Agha
1   University of Petra, College of Pharmacy, Amman, Jordan
,
Tawfiq Arafat
1   University of Petra, College of Pharmacy, Amman, Jordan
› Author Affiliations
Further Information

Publication History

received 14 May 2017

accepted 26 July 2017

Publication Date:
28 August 2017 (online)

Also available at
   Permissions and Reprints

Abstract

Aim The aim of this study is to investigate the robustness of using non-invasive saliva instead of plasma for bioequivalence of valsartan and hydrochlorothiazide (HCT) in humans based on Salivary Excretion Classification System (SECS).

Methods Plasma and resting saliva samples were collected over 24 h after oral administration of single dose 160 mg valsartan and 12.5 mg HCT to 12 healthy male volunteers after 10 h overnight fasting. Plasma and saliva concentrations were determined by validated liquid chromatography-mass spectrometry. WinNonlin program V5.2 was used to determine pharmacokinetic parameters and bioequivalence metrics. Moreover, optimized effective intestinal permeability was estimated using PK-Sim/Mobi program V5.6.

Results and Discussion Valsartan is SECS class IV drug due of low permeability and high protein binding and hence didn’t appear in saliva. However, HCT is SECS class II drug due to low permeability and low protein binding. No significant differences were observed in the pharmacokinetic parameters in both plasma matrix and saliva matrix (P˃0.05). The 90% confidence intervals did not pass in all parameters due to the high intra-subject variability and small sample size used in this study. Saliva to plasma ratios of HCT were low, yet with high correlation coefficient of 0.96–0.98. So saliva can be used as alternative to plasma sample in pharmacokinetic studies and in bioequivalence when adequate sample size is used.

Key words

salivary excretion classification system - valsartan/hydrochlorothiazide - bioequivalence - pharmacokinetics - Pk-Sim/MoBi
 

  • References

  • 1 Idkaidek N, Arafat T. Saliva versus plasma pharmacokinetics: Theory and application of a salivary excretion classification system. Molecular pharmaceutics 2012; 9: 2358-2363
    CrossrefPubMedGoogle Scholar
  • 2 Ashavaid T, Dheraj A. Therapeutic drug monitoring—A review. Indian Journal of Clinical Biochemistry 1999; 14: 91-94
    CrossrefPubMedGoogle Scholar
  • 3 Danhof M, Breimer D. Therapeutic drug monitoring in saliva. Clinical pharmacokinetics 1978; 3: 39-57
    CrossrefPubMedGoogle Scholar
  • 4 Drobitch RK, Svensson CK. Therapeutic drug monitoring in saliva. Clinical pharmacokinetics 1992; 23: 365-379
    CrossrefPubMedGoogle Scholar
  • 5 Liu H, Delgado MR. Therapeutic drug concentration monitoring using saliva samples. Clinical pharmacokinetics 1999; 36: 453-470
    CrossrefPubMedGoogle Scholar
  • 6 Kaufman E, Lamster IB. The diagnostic applications of saliva—a review. Critical Reviews in Oral Biology & Medicine 2002; 13: 197-212
    CrossrefPubMedGoogle Scholar
  • 7 Mandel ID. The diagnostic uses of saliva. Journal of Oral Pathology & Medicine 1990; 19: 119-125
    CrossrefPubMedGoogle Scholar
  • 8 Elmongy H, Abdel-Rehim M. Saliva as an alternative specimen to plasma for drug bioanalysis: A review. TrAC Trends in Analytical Chemistry 2016; 83: 70-79
    CrossrefPubMedGoogle Scholar
  • 9 Van Oosten M, Notten F, Mikx F. Metronidazole concentrations in human plasma, saliva, and gingival crevice fluid after a single dose. Journal of dental research 1986; 65: 1420-1423
    CrossrefPubMedGoogle Scholar
  • 10 Matin SB, Wan SH, Karam JH. Pharmacokinetics of tolbutamide: prediction by concentration in saliva. Clinical Pharmacology & Therapeutics 1974; 16: 1052-1058
    CrossrefPubMedGoogle Scholar
  • 11 Kumar AH, Gurumurthy P. Ofloxacin pharmacokinetics in saliva. Indian journal of pharmacology 2004; 36: 80
    PubMedGoogle Scholar
  • 12 Criscione L, Gasparo M, Buhlmayer P. et al. Pharmacological profile of valsartan: A potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. British journal of pharmacology 1993; 110: 761-771
    CrossrefPubMedGoogle Scholar
  • 13 Flesch G, Muller P, Lloyd P. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. European journal of clinical pharmacology 1997; 52: 115-120
    CrossrefPubMedGoogle Scholar
  • 14 Wellington K, Faulds DM. Valsartan/hydrochlorothiazide. Drugs 2002; 62: 1983-2005
    CrossrefPubMedGoogle Scholar
  • 15 Prasad PP, Yeh C-M, Gurrieri P. et al. Pharmacokinetics of multiple doses of valsartan in patients with heart failure. Journal of cardiovascular pharmacology 2002; 40: 801-807
    CrossrefPubMedGoogle Scholar
  • 16 Black HR, Bailey J, Zappe D. et al. Valsartan. Drugs 2009; 69: 2393-2414
    CrossrefPubMedGoogle Scholar
  • 17 Sica DA, Carter B, Cushman W. et al. Thiazide and loop diuretics. The journal of clinical hypertension 2011; 13: 639-643
    CrossrefPubMedGoogle Scholar
  • 18 Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman's The pharmacological basis of therapeutics. 2011. New York: McGraw-Hill Medical; pp 689-690 769-770, 736
    Google Scholar
  • 19 Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. The AAPS journal 2009; 11: 740-746
    CrossrefPubMedGoogle Scholar
  • 20 Challa VR, Ravindra Babu P, Challa SR. et al. Pharmacokinetic interaction study between quercetin and valsartan in rats and in vitro models. Drug development and industrial pharmacy 2013; 39: 865-872
    CrossrefPubMedGoogle Scholar
  • 21 Lozoya-Agullo I, González-Álvarez I, González-Álvarez M. et al In Situ Perfusion Model in Rat Colon for Drug Absorption Studies: Comparison with Small Intestine and Caco-2 Cell Model. Journal of pharmaceutical sciences 2015; 104: 3136-3145
    CrossrefPubMedGoogle Scholar