A physiologically based pharmacokinetic model for nicotine disposition in the Sprague-Dawley rat

https://doi.org/10.1016/0041-008X(92)90297-6Get rights and content

Abstract

A physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition of nicotine in the Sprague-Dawley (SD) rat. Parameters for the model were either obtained from the literature (blood flows, organ volumes) or determined experimentally (partition coefficients). Nicotine metabolism was defined in the liver compartment by the first-order rate constants KNC and KNP which control the rate of nicotine metabolism to cotinine and “polar metabolites” (PM), respectively. These rate constants were estimated by optimizing the model fit to pharmacokinetic data obtained by administering an intraarterial (S)-[5-3H] nicotine bolus of 0.1 mg/kg to 6 rats. Model simulations that optimized for the appearance of cotinine in plasma estimated KNC and KNP to be 75.8 and 24.3 hr−1, respectively. Use of these constants in the model allowed us to accurately predict nicotine plasma kinetics and the fraction of the dose eliminated by renal (8.5%) and metabolic (91.5%) clearance. To validate the model's ability to predict tissue kinetics of nicotine, 21 male SD rats were administered 0.1 mg/kg (S)-[5-3H] nicotine intraarterially. At seven time points following treatment, 3 rats were euthanized and tissues were removed and analyzed for nicotine. Model-predicted nicotine tissue kinetics were in agreement with those determined experimentally in muscle, liver, skin, fat, and kidney. The brain, heart, and lung exhibited nonlinear nicotine elimination, suggesting that saturable nicotinic binding sites may be important in nicotine disposition in these organs. Inclusion of saturable receptor binding expressions in the mathematical description of these compartments resulted in better agreement with the experimental data. The Bmax and KD estimated by model simulation for these tissues were brain, 0.009 and 0.12; lung, 0.039 and 2.0; and heart, 0.039 nmol/tissue and 0.12 nm, respectively. This PBPK model can succesfully describe the tissue and plasma kinetics of nicotine in the SD rat and will be a useful tool for pharmacologic studies in humans and experimental animals that require insight into the plasma or tissue concentration-effect relationship.

References (57)

  • J.C. Ramsey et al.

    A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans

    Toxicol. Appl. Pharmacol.

    (1984)
  • R.H. Reitz et al.

    In vitro metabolism of methylene chloride in human and animal tissues: Use in physiologically based pharmacokinetic model

    Toxicol. Appl. Pharmacol.

    (1989)
  • K.S. Rotenberg et al.

    Pharmacokinetics of nicotine in rats after single-cigarette smoke inhalation

    J. Pharm. Sci.

    (1980)
  • S.L. Schwartz et al.

    Mathematical modelling of nicotine and cotinine as biological markers of environmental tobacco smoke exposure

    Toxicol. Lett.

    (1987)
  • C. Su

    Actions of nicotine and smoking on circulation

    Pharmacol. Ther.

    (1982)
  • A. Tsujimoto et al.

    Toxicol. Appl. Pharmacol.

    (1975)
  • J. Adir et al.

    Disposition of nicotine in the rat after intravenous administration

    Res. Commun. Chem. Pathol. Pharmacol.

    (1976)
  • G. Andersson et al.

    Gastric excretion of C14-nicotine

    Experimentia

    (1965)
  • N.L. Benowitz et al.

    Interindividual variability in the metabolism and cardiovascular effects of nicotine in man

    J. Pharmacol. Exp. Ther.

    (1982)
  • N.L. Benowitz et al.

    Nicotine renal excretion rate influences nicotine intake during cigarette smoking

    J. Pharmacol. Exp. Ther.

    (1985)
  • N.L. Benowitz

    The human pharmacology of nicotine

    Res. Adv. Alcohol Drug Prob.

    (1986)
  • N.L. Benowitz et al.

    Pharmacokinetics, metabolism, and pharmacodynamics of nicotine

  • N.L. Benowitz et al.

    Stable isotope studies of nicotine kinetics and bioavailability

    Clin. Pharmacol. Ther.

    (1991)
  • Byrd

    Evidence for urinary excretion of glucuronide conjugates of nicotine, cotinine, and trans-3′-hydroxycotinine in smokers

    Drug Metab. Dispos.

    (1992)
  • CDC

    Cigarette smoking in the United States, 1986

    Morbidity Mortality Weekly Rep.

    (1987)
  • G.H.-S. Chen et al.

    Estimation of tissue-to-plasma partition coefficients used in physiological pharmacokinetic models

    J. Pharmacokinet. Biopharm.

    (1979)
  • P.B.S. Clarke

    The central pharmacology of nicotine: electrophysiological approaches

  • J.D. deBethizy et al.

    A physiologically based pharmacokinetic model for nicotine in the rat

    Toxicologist

    (1990)
  • Cited by (72)

    • Deconvolution of Systemic Pharmacokinetics Predicts Inhaled Aerosol Dosimetry of Nicotine

      2023, European Journal of Pharmaceutical Sciences
      Citation Excerpt :

      Our PBPK model also predicted longer nicotine terminal elimination half-life due to the slow release of nicotine from lysosomes back into the systemic circulation. However, nicotine is also known to bind to receptors, and earlier PBPK models developed for different routes of administration have incorporated receptor binding to predict tissue distribution (Plowchalk et al., 1992; Robinson et al., 2005; Rostami et al., 2022; Teeguarden et al., 2013; Yang et al., 2020). These PBPK models were able to capture the rapid clearance of high systemic nicotine concentrations in different species but were unable to describe the terminal plasma nicotine concentrations (Yang et al., 2020).

    • Use of a physiologically-based pharmacokinetic model to explore the potential disparity in nicotine disposition between adult and adolescent nonhuman primates

      2020, Toxicology and Applied Pharmacology
      Citation Excerpt :

      Thus, age-dependent changes for nicotine pharmacokinetics between human adults and youth warrant further evaluation. A number of PBPK models have been developed to describe the pharmacokinetics of nicotine and cotinine in rats (Plowchalk et al., 1992; Teeguarden et al., 2013; Saylor and Zhang, 2016) and humans (Robinson et al., 1992; Clewell et al., 2004; Yamazaki et al., 2010; Teeguarden et al., 2013; Gajewska et al., 2014; Saylor and Zhang, 2016), which focused primarily on adults. In addition to evaluating the kinetics of nicotine and cotinine across different exposure pathways, the model developed by Saylor et al. investigated the effect of anti-nicotine antibody on nicotine disposition in the brain with the description of antibody association and disassociation with nicotine (Saylor and Zhang, 2016).

    View all citing articles on Scopus
    View full text