Population pharmacokinetic analysis of carboxyhaemoglobin concentrations in adult cigarette smokers

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The pharmacokinetics of carboxyhaemoglobin have been reported previously, primarily with regard to poisoning and toxicity.• Most of these reports have involved noncompartmental analysis of data obtained where the actual dose of carbon monoxide was not known. WHAT THIS STUDY ADDS• This study presents a comprehensive population pharmacokinetic model for carboxyhaemoglobin in adult cigarette smokers.• Since carboxyhaemoglobin is a marker of cigarette smoke exposure, model-based evaluations can be used for simulation and other evaluations of the kinetics of this agent. AIMSTo develop a population-based model to describe and predict the pharmacokinetics of carboxyhaemoglobin (COHb) in adult smokers. METHODSData from smokers of different conventional cigarettes (CC) in three open-label, randomized studies were analysed using NONMEM (version V, Level 1.1). COHb concentrations were determined at baseline for two cigarettes [Federal Trade Commission (FTC) tar 11 mg; CC1, or FTC tar 6 mg; CC2]. On day 1, subjects were randomized to continue smoking their original cigarettes, switch to a different cigarette (FTC tar 1 mg; CC3), or stop smoking. COHb concentrations were measured at baseline and on days 3 and 8 after randomization. Each cigarette was treated as a unit dose assuming a linear relationship between the number of cigarettes smoked and measured COHb percent saturation. Model building used standard methods. Model performance was evaluated using nonparametric bootstrapping and predictive checks. RESULTSThe data were described by a two-compartment model with zero-order input and first-order elimination with endogenous COHb. Model parameters included elimination rate constant (k10), central volume of distribution (Vc/F), rate constants between central and peripheral compartments (k12 and k21), baseline COHb concentrations (c0), and relative fraction of carbon monoxide absorbed (F1). The median (range) COHb half-lives were 1.6 h (0.680-2.76) and 30.9 h (7.13-367) (a and b phases, respectively). F1 increased with increasing cigarette tar content and age, whereas k12 increased with ideal body weight. CONCLUSIONA robust model was developed to predict COHb concentrations in adult smokers and to determine optimum COHb sampling times in future studies.

Blood haemoglobin concentrations are higher in smokers and heavy alcohol consumers than in non-smokers and abstainers—should we adjust the reference range?

“…In our series, men smoking >10 cigarettes/day had a 1.4% increase in haemoglobin compared to non-smokers, whereas in women, the increase was on the average 3.5%, which is in accordance with the carboxyhaemoglobin levels of 3-6% reported in smokers [14,17]. "Normalization" of haemoglobin after smoking cessation has likewise been reported in humans [7,8].…”

Anesthesia implications of waterpipe use

“…The amount of COHb in the blood depends on duration of CO exposure, CO concentration in inspired air, and alveolar ventilation [6]. Similarly, elimination half-life depends on duration of exposure, concentration, alveolar ventilation, and peak level of COHb [5,6,9]. Most available data for COHb half-life are from acute exposures where subjects were administered supplemental oxygen; these data have suggested a relatively short half-life of 74 to 137 minutes [5].…”

“…Carbon monoxide is a tasteless and odorless gas that binds to Hb with an affinity more than 200 times that of O 2 ; CO actively displaces O 2 from Hb to form COHb [5,6]. Carbon monoxide inhaled by smoking may cause tissue hypoxia both by this decrease in blood O 2 content and also by a COinduced shift in the O 2 -Hb dissociation curve to the left, which impedes release of O 2 to tissues [7,8].…”

Carbon monoxide in biological systems: an experimental and clinical study

“…In another study, kinetics for CO elimination in smokers has been investigated. The result showed two-compartmental kinetics with half-life of 1.6 h for the first phase and 30.9 h for the second phase (Cronenberger et al, 2007). One study suggests that blood donors avoid cigarettes for 24 h before blood donation.…”

“…Some have claimed that CO follows first orders kinetics with one compartmental elimination (Kreck et al, 2001;Sasaki, 1975;Weaver et al, 2000), while others speculate that it has second or multi-compartmental elimination (Shimazu et al, 2000;Wagner et al, 1975); (Wazawa et al, 1996). In a population pharmacokinetic study investigating the elimination time for CO in smokers, the results showed twocompartmental kinetics with a half-life of 1.6 h for the first phase and 30.9 h for the second phase (Cronenberger, Mould, Roethig, & Sarkar, 2007). In that study 190 smokers participated and a mathematic model to predict COHb fractions in adult smokers was developed.…”