Estimating the Fraction Dose Absorbed from Suspensions of Poorly Soluble Compounds in Humans: A Mathematical Model

A microscopic mass balance approach has been developed to predict the fraction dose absorbed of suspensions of poorly soluble compounds. The mathematical model includes four fundamental di-mensionless parameters to estimate the fraction dose absorbed: initial saturation (Is), absorption number (An), dose number (Do), and dissolution number (Dn). The fraction dose absorbed (F) increases with increasing Is, An, and Dn and with decreasing Do. At higher Dn and lower Do, the fraction dose absorbed reaches the maximal F, which depends only on An. The dissolution number limit on F can appear at both lower Do and lower Dn. Likewise, at higher Do and Dn, the fraction dose absorbed reaches a Do limit. Initial saturation makes a significant difference in F at lower Do and Dn. It is shown that the extent of drug absorption is expected to be highly variable when Dn and Do are approximately one. Furthermore, by calculating these dimensionless groups for a given compound, a formulation scientist can estimate not only the extent of drug absorption but also the effect, if any, of particle size reduction on the extent of drug absorption.     

Effects of Intestinal CYP3A4 and P-Glycoprotein on Oral Drug Absorption—Theoretical Approach

Purpose. To evaluate the effects of gut metabolism and efflux on drug absorption by simulation studies using a pharmacokinetic model involving diffusion in epithelial cells. Methods. A pharmacokinetic model for drug absorption was constructed including metabolism by CYP3A4 inside the epithelial cells, P-gp-mediated efflux into the lumen, intracellular diffusion from the luminal side to the basal side, and subsequent permeation through the basal membrane. Partial differential equations were solved to yield an equation for the fraction absorbed from gut to the blood. Effects of inhibition of CYP3A4 and/or P-gp on the fraction absorbed were simulated for a hypothetical substrate for both CYP3A4 and P-gp. Results. The fraction absorbed after oral administration was shown to increase following inhibition of P-gp. This increase was more marked when the efflux clearance of the drug was greater than the sum of the metabolic and absorption clearances and when the intracellular diffusion constant was small. Furthermore, it was demonstrated that the fraction absorbed was synergistically elevated by simultaneous inhibition of both CYP3A4 and P-gp. Conclusions. The analysis using our present diffusion model is expected to allow the prediction of in vivo intestinal drug absorption and related drug interactions from in vitro studies using human intestinal microsomes, gut epithelial cells, CYP3A4-expressed Caco-2 cells, etc.     

Effect of micronization on the extent of drug absorption from suspensions in humans

A microscopic mass balance approach has shown that the initial saturation (Is), absorption number (An), dose number (Do), and dissolution number (Dn) are four fundamental dimensionless parameters that can be used to estimate the fraction dose absorbed (F) of suspensions of poorly soluble drugs in humans. The dissolution number of a drug increases with decreasing its particle size. The effect of micronization onF for suspensions was investigated in terms ofDn. About 90% of maximalF can be achieved atDn≈2. Increasing the solubility of a drug results in better oral absorption through increasingDn and decreasingDo. The fractions dose absorbed of digoxin, griseofulvin, and benoxaprofen agree with predictedF values using estimated parameters. Drugs with lowDo and lowDn can be more completely absorbed by reducing particle size, while absorption of drugs with highDo and lowDn is limited by solubility and requires higher solubility to enhance the fraction dose absorbed in addition to micronization. Solubility at the physiological pH should be used for the estimation of the fraction dose absorbed.     

Predicting Oral Absorption of Drugs: A Case Study with a Novel Class of Antimicrobial Agents

Purpose. The purpose of this work was to evaluate an oral absorption prediction model, maximum absorbable dose (MAD), which predicts a theoretical dose of drug that could be absorbed across rat intestine based on consideration of intestinal permeability, solute solubility, intestinal volume, and residence time. Methods. In the present study, Caco-2 cell permeability, as a surrogate for rat intestinal permeability, and aqueous solubility were measured for 27 oxazolidinones. The oxazolidinones are a novel class of potential antibacterial agents currently under investigation. These values were used to estimate MAD for each of the compounds. Finally, these predicted values were compared to previously measured bioavailability data in the rat in order to estimate oral absorption properties. Results. A reasonably good correlation between predicted dose absorbed and bioavailability was observed for most of the compounds. In a few cases involving relatively insoluble compounds, absorption was underestimated. For these compounds while aqueous solubility was low, solubility in 5% polysorbate 80 was significantly higher, a solvent possibly more representative of the small intestinal lumen. Conclusions. These results suggest that MAD may be useful for prioritizing early discovery candidates with respect to oral absorption potential. In the case of compounds with poor aqueous solubility, additional factors may have to be considered such as solubility in the intestinal lumen.     

Method to Estimate the Rate and Extent of Intestinal Absorption in Conscious Rats Using an Absorption Probe and Portal Blood Sampling

Purpose. A variety of methods exist which determine the rate and extent of intestinal absorption. The method described here employs an internal absorption reference probe and portal blood sampling in unanesthetized rat. Methods. Theophylline and tritiated water were selected as absorption reference probes since they are quantitatively absorbed in conscious rat. The fraction of an intestinal dose which reaches portal blood was determined from the resulting portal-systemic blood concentration gradients of the drug relative to the absorption probe. The absorption probes provide a means to calculate the drug mass reaching portal blood without the need of measuring the portal blood flow rate. The technique was evaluated with verapamil and a well-absorbed 5-lipoxygenase inhibitor, A-79035. Results. The fraction of an intrajejunal dose of A-79035 reaching the portal vein (F_G) was 0.86 using theophylline as the absorption probe. Verapamil, which is susceptible to extensive hepatic first-pass elimination, was completely absorbed (F_G = 0.98) within 1 hour, but was only 21.4% bioavailable. Absorption rate constants, estimated from initial appearance rates in portal blood, were used to monitor factors that affect drug absorption. For example, with a dose solution containing 30% PEG-400, the absorption rate constants of theophylline and A-79035 were significantly reduced. Anesthesia reduced the absorption rate constant for theophylline in rats by 40% compared to conscious animals. Conclusions. The technique detailed here allows reliable, direct measurement of intestinal absorption which may assist in characterizing oral dosing for novel therapeutic agents.     

Evaluation of Using Dog as an Animal Model to Study the Fraction of Oral Dose Absorbed of 43 Drugs in Humans

Purpose. To conduct a retrospective evaluation of using dog as ananimal model to study the fraction of oral dose absorbed (F) of 43drugs in humans and to briefly discuss potential factors that mighthave contributed to the observed differences in absorption. Methods. Mean human and dog absorption data obtained under fastedstate of 43 drugs with markedly different physicochemical andpharmacological properties and with mean F values ranging from 0.015 to1.0 were obtained from the literature. Correlation of F values betweenhumans and dogs was studied. Based on the same references, additionalF data for humans and rats were also obtained for 18 drugs. Results. Among the 43 drugs studied, 22 drugs were virtuallycompletely absorbed in both dogs and humans. However, the overallcorrelation was relatively poor (r² = 0.5123) as compared to the earlier ratvs. human study on 64 drugs (r² = 0.975). Several drugs showed muchbetter absorption in dogs than in humans. Marked differences in thenonliner absorption profiles between the two species were found forsome drugs. Also, some drugs had much longer T_max values andprolonged absorption in humans than in dogs that might be theoreticallypredicted. Data on 18 drugs further support great similarity in F betweenhumans and rats reported earlier from our laboratory. Conclusions. Although dog has been commonly employed as ananimal model for studying oral absorption in drug discovery anddevelopment, the present study suggests that one may need to exercise cautionin the interpretation of data obtained. Exact reasons for the observedinterspecies differences in oral absorption remain to be explored.     

Estimating Human Oral Fraction Dose Absorbed: A Correlation Using Rat Intestinal Membrane Permeability for Passive and Carrier-Mediated Compounds

Based on a simple tube model for drug absorption, the key parameters controlling drug absorption are shown to be the dimensionless effective permeability, P _eff ^*, and the Graetz number, Gz, when metabolism or solubility/dissolution is not rate controlling. Estimating the Graetz number in humans and assuming that P _aq ^* is not rate controlling gives the following equation for fraction dose absorbed: F = 1– e ^{–2 P*w}. The correlation between fraction dose absorbed in humans and P _w ^* determined from steady-state perfused rat intestinal segments gives an excellent correlation. It is of particular significance that the correlation includes drugs that are absorbed by passive and carrier-mediated processes. This indicates that P _w ^* is one of the key variables controlling oral drug absorption and that the correlation may be useful for estimating oral drug absorption in humans regardless of the mechanism of absorption.     

Development and Validation of a Physiology-based Model for the Prediction of Oral Absorption in Monkeys

Purpose The development and validation of a physiology-based absorption model for orally administered drugs in monkeys is described. Materials and Methods Physiological parameters affecting intestinal transit and absorption of an orally administered drug in monkeys have been collected from the literature and implemented in a physiological model for passive absorption previously developed for rats and humans. Predicted fractions of dose absorbed have been compared to experimentally observed values for a set of N = 37 chemically diverse drugs. A sensitivity analysis was performed to assess the influence of various physiological model parameters on the predicted fraction dose absorbed. Results A Pearson’s correlation coefficient of 0.94 (95% confidence interval: [0.88, 0.97]; p < 0.0001) between the predicted and observed fraction dose absorbed in monkeys was obtained for compounds undergoing non-solubility limited passive absorption (N = 29). The sensitivity analysis revealed that the predictions of fractions dose absorbed in monkeys are very sensitive with respect to inter-individual variations of the small intestinal transit time. Conclusions The model is well suited to predict the fraction dose absorbed of passively absorbed compounds after oral administration and to assess the influence of inter-individual physiological variability on oral absorption in monkeys.     

Bias in the Wagner–Nelson Estimate of the Fraction of Drug Absorbed

Purpose. To examine and quantify bias in the Wagner-Nelson estimate of the fraction of drug absorbed resulting from the estimation error of the elimination rate constant (k), measurement error of the drug concentration, and the truncation error in the area under the curve. Methods. Bias in the Wagner-Nelson estimate was derived as a function of post-dosing time (t), k, ratio of absorption rate constant to k (r), and the coefficient of variation for estimates of k (CV _k), or CV _c for the observed concentration, by assuming a one-compartment model and using an independent estimate of k. The derived functions were used for evaluating the bias with r= 0.5, 3, or 6; k= 0.1 or 0.2; CV _c = 0.2 or 0.4; and CV _k =0.2 or 0.4; for t= 0 to 30 or 60. Results. Estimation error of k resulted in an upward bias in the Wagner-Nelson estimate that could lead to the estimate of the fraction absorbed being greater than unity. The bias resulting from the estimation error of k inflates the fraction of absorption vs. time profiles mainly in the early post-dosing period. The magnitude of the bias in the Wagner-Nelson estimate resulting from estimation error of k was mainly determined by CV _k. The bias in the Wagner-Nelson estimate resulting from to estimation error in k can be dramatically reduced by use of the mean of several independent estimates of k, as in studies for development of an in vivo-in vitro correlation. The truncation error in the area under the curve can introduce a negative bias in the Wagner-Nelson estimate. This can partially offset the bias resulting from estimation error of k in the early post-dosing period. Measurement error of concentration does not introduce bias in the Wagner-Nelson estimate. Conclusions. Estimation error of k results in an upward bias in the Wagner-Nelson estimate, mainly in the early drug absorption phase. The truncation error in AUC can result in a downward bias, which may partially offset the upward bias due to estimation error of k in the early absorption phase. Measurement error of concentration does not introduce bias. The joint effect of estimation error of k and truncation error in AUC can result in a non-monotonic fraction-of-drug-absorbed-vs-time profile. However, only estimation error of k can lead to the Wagner-Nelson estimate of fraction of drug absorbed greater than unity.     

Guidance in the Setting of Drug Particle Size Specifications to Minimize Variability in Absorption

Purpose. To provide guidance in setting particle size specifications for poorly soluble drugs to minimize variability in absorption. Methods. A previously reported computer method was used to simulate the percent of dose absorbed as a function of solubility, absorption rate constant, dose, and particle size. Results. The simulated percent of dose absorbed was tabulated over a realistic range of solubilities, absorption rate constants, and doses using drug particle sizes that might be typically found in a dosage form. Conclusions. The greatest effect of particle size on absorption was simulated for low dose- low solubility drugs. In general, the sensitivity of absorption to particle size decreased with increasing dose or solubility. At a solubility of 1 mg/mL, particle size had practically no effect on the percent of dose absorbed over the range of doses simulated (1–250 mg).     

Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans

Purpose. A theoretical method has been devised for prediction of drug absorption after oral administration to humans. Methods. Twenty structurally diverse model drugs, ranging from 0.3 to 100% absorbed, were investigated. The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and molecular size. The dynamic molecular surface properties of the compounds were calculated, taking into account their three-dimensional shape and flexibility. Results. An excellent sigmoidal relationship was established between the absorbed fraction after oral administration to humans (FA) and the dynamic polar molecular surface area (PSA_d) (r² = 0.94). The relationship was stronger than those obtained for more established predictors of drug absorption. Drugs that are completely absorbed (FA > 90%) had a PSA_d 60 ² while drugs that are < 10% absorbed had a PSA_d > 140 ². Conclusions. The results indicate that PS Ad can be used to differentiate poorly absorbed drugs at an early stage of the drug discovery process.     

Enhanced Oral Bioavailability of DDI After Administration of 6-Cl-ddP,an Adenosine Deaminase-Activated Prodrug,to Chronically Catheterized Rats

Purpose. 6-Cl-2,3-dideoxypurine (6-Cl-ddP), an adenosine deaminase (ADA) activated prodrug of ddI, may be an effective antiretroviral agent for the treatment of AIDS dementia due to its ability to deliver increased concentrations of ddI to brain tissue. To examine the feasibility of administering this drug orally, the oral and hepatic portal bioavailabilities of 6-Cl-ddP were determined. In addition, the oral and portal bioavailabilities of ddI after administration of the prodrug were compared to those from administration of ddI itself. Methods. Pharmacokinetic and bioavailability studies were conducted in fully conscious, chronically catheterized rats in a randomized crossover design. Plasma ddI and 6-Cl-ddP concentration-time profiles were determined by HPLC. Results. 6-Cl-ddP has poor apparent oral bioavailability (7% ± 3%, n = 3) but high bioavailability after portal administration (97% ± 11%), suggesting either poor absorption or extensive gut wall metabolism. The appearance of >50% of the dose as ddI in the systemic circulation after an oral dose of 6-Cl-ddP rules out poor absorption of the prodrug, and confirms expectations of high ADA activity in the gastrointestinal tract. Gastric administration of 6-Cl-ddP resulted in a > 10-fold increase in the oral bioavailability of ddI, from 3–7% to >50%, and a significant decrease in the variability in apparent bioavailability. Conclusions. These data indicate that lipophilic adenosine deaminase activated prodrugs of dideoxypurine nucleosides may have limited utility for improving CNS delivery after oral administration but may be useful in enhancing the oral bioavailability of highly polar and therefore poorly absorbed dideoxynucleosides.     

A compartmental absorption and transit model for estimating oral drug absorption.

This report describes a compartmental absorption and transit model to estimate the fraction of dose absorbed and the rate of drug absorption for passively transported drugs in immediate release products. The model considers simultaneous small intestinal transit flow and drug absorption. Both analytical and numerical methods were utilized to solve the model equations. It was found that the fraction of dose absorbed can be estimated by F(a) = 1-(1+0.54 P(eff))(-7), where P(eff) is the human effective permeability in cm/h. A good correlation was found between the fraction of dose absorbed and the effective permeability for ten drugs covering a wide range of absorption characteristics. The model was able to explain the oral plasma concentration profiles of atenolol.     

Exploring a Kinetic Model Approach in Biopharmaceutics: Estimating the Fraction Absorbed of Orally Administered Drugs in Humans

Increasing costs of research and development in the pharmaceutical industry has necessitated a growing interest in the early prediction of human pharmacokinetics of drug candidates. Of growing interest is the need to understand oral absorption, the most common route of small molecule drug administration. The fraction of dose absorbed (%Fa) is considered a critical yet challenging parameter to predict. A kinetic model has been developed and tested to provide an early prediction of the fraction dose absorbed in humans. Unlike the traditional plug-flow model, this model assumes first-order kinetics to estimate the amount of drug present in the stomach and small intestine as a function of time and calculates the amount of drug released and absorbed during the transit. Other variables can be included in calculation as a function of time to better mimic the physiological condition with this approach. Absorption efficiency is assigned along with %Fa to give a quantitative estimate of the limiting factor for oral absorption. The model was tested with literature and in-house compounds. It was found that this model gives a good prediction of human %Fa with a correction coefficient (R²) of 0.8 and greater between predicted and reported %Fa for all compounds.     

Perfusion Cells for Studying Regional Variation in Oral-Mucosal Permeability in Humans. I: Kinetic Aspects in Oral-Mucosal Absorption of Alkylparabens

Purpose. To evaluate regional differences in permeability of human oral mucosa. Methods. Newly designed perfusion cells were used for the investigation. The cells were applied to 5 different sites, i.e., dorsum of tongue, ventral surface of tongue, labial mucosa, floor of mouth and buccal mucosa of human volunteers. Model drugs used were methyl-, ethyl-, propyl- and butylparaben, which are passively absorbed from oral mucosa and have different lipophilicities. Biexponential disappearance profiles of the alkylparabens were analyzed kinetically using a two-compartment linear open model. Results. Both the partitioning parameters to the oral mucosa and the absorption rate constants to the blood circulation correlated to the lipophilicities of the compounds in all mucosa. As to the former parameter, no significant difference was recognized in all mucosa. While, the latter parameter exhibited the regional difference; the absorption rate constants in buccal mucosa were approximately one-half of those estimated in other oral mucosa. A positive relation was recognized between the retention in oral-mucosal compartment and the drug lipophilicity. Conclusions. The newly designed perfusion cells used in this study were useful to examine the regional variations of drug absorption from oral mucosa in humans. The absorption rate constant, the partition to oral mucosa and the residence time in oral mucosa increased with lipophilicity of the compound. The regional difference in the drug absorption process was demonstrated; the slow absorption and the prolonged retention were demonstrated in buccal mucosa.     

Extensive Absorption of 2′,3′-Dideoxyinosine by Intratracheal Administration in Rats

Purpose. To evaluate the intratracheal route of administration as an alternative to oral administration for 2,3-dideoxyinosine (ddI). Methods. A ddI dose (40 mg/kg/300 µl or 6.5 mg/kg/50 µl) was instilled into the trachea in female Fisher rats and an intravenous tracer dose (9 µg/kg) of ³H-ddI was administered concomitantly to determine the drug clearance. Plasma concentrations were analyzed for the rate and extent of absorption. Results. ddI was rapidly absorbed from the lungs, with a bioavailability of 63% at 40 mg/kg and 101% at 6.5 mg/kg. By comparison, our previous data showed an oral bioavailability of about 15% (Pharm Res., 9:822, 1992). The distribution of a dye solution instilled intratracheally showed that a fraction of the 300 µL dose spilled over to the gastrointestinal tract, where the entire 50 µL dose was retained in the lungs. The different distribution of the two doses/volumes likely contributed to the different bioavailability, with a fraction of the higher dose/volume degraded in the gastrointestinal tract after the spillover. Absorption of ddI from the airspace of the lung was biexponential, suggesting two absorption processes. Conclusions. These data indicate significantly higher and less variable bioavailability of ddI by the intratracheal route of delivery compared to the oral route. Furthermore, the complete bioavailability at the lower dose/volume indicates no significant pulmonary first pass elimination for ddI.     

Concurrent intravenous administration of a labeled tracer to determine the oral bioavailability of a drug exhibiting Michaelis-Menten metabolism

The theoretical accuracy of concurrent administration of labeled intravenous tracer and oral doses to estimate the bioavailability of drugs exhibiting Michaelis-Menten kinetics was determined by computer simulation. The simulation model consisted of sampling and hepatic compartments with elimination occurring by hepatic metabolism according to the venous equilibration model. The relationships between error in bioavailability estimation and dose, metabolic activity (V_max),first-order absorption rate constant (k _a), and volume of distribution (V) and the fraction of the dose absorbed were examined. Error was hypothesized to be relatively low when conditions result in a relatively constant value of clearance after oral dosing or when the concentration-time curves after intravenous and oral dosing are similar. The results were consistent with these hypotheses and, under most conditions, error was less than 15%. The effects, on error, of altering the intravenous tracer dose input and having a lag time in absorption of drug from the oral dose were also determined. In general, accuracy was improved by delaying administration of the iv tracer for a time equal to 50% of the oral dose peak time or by administering the tracer dose by constant-rate infusion from the time of oral dosing to the peak time. Lag time in absorption of the oral dose was shown to often result in overestimates in bioavailability of greater than 50%.This work was supported in part by grants GM 26556 and GM 07175 from the Institute of General Medical Sciences of the National Institutes of Health.     

The Role of Metabolites in Bioequivalency Assessment. III. Highly Variable Drugs with Linear Kinetics and First-Pass Effect

Purpose. Simulated pharmacokinetic (PK) studies were done to determine the effect of intrinsic clearance (CL_INT) on the probability of meeting bioequivalence criteria for extent (AUC) and rate (Cmax) of drug absorption when the absorption rate and fraction absorbed (F) were formulated either to be equivalent or to differ by 25%. Methods. Simulated PK studies were done using a linear first-pass model with CL_INT values ranging from 15 L/HR to 900 L/HR. Test/Reference absorption rate constants (Ka) and fraction absorbed (Fa) ratios of 1.0 or 1.25 were used for all simulations. The impact of the value of CL_INT and its intrasubject variation upon the probability of concluding bioequivalence at the two different Ka and F ratios was studied. Additionally, the effect of fraction metabolized i.v., (Fm) on the probabilities of concluding equivalence was studied at values of 0.25 and 0.75. Results. When CL_INT values were raised above those for liver blood flow, the frequency of trials in which bioequivalence was correctly declared decreased when parent AUC was used as a bioequivalence criterion. Only when CL_INT exceeded liver blood flow did the metabolite become important in assessing extent of absorption. Conclusions. The Cmax for the parent drug provided the most accurate assessment of bioequivalence. The Cmax for the metabolite was insensitive to changes related to rate of input, and when CL_INT exceeded liver blood flow, evaluation of the metabolite Cmax data may lead to a conclusion of bioequivalence for products that were not.     

A Heterogeneous Tube Model of Intestinal Drug Absorption Based on Probabilistic Concepts

Purpose. To develop an approach based on computer simulations for the study of intestinal drug absorption. Methods. The drug flow in the gastrointestinal tract was simulated with a biased random walk model in the heterogeneous tube model Pharm. Res. 16, 87-91, 1999), while probability concepts were used to describe the dissolution and absorption processes. An amount of drug was placed into the input end of the tube and allowed to flow, dissolve and absorb along the tube. Various drugs with a diversity in dissolution and permeability characteristics were considered. The fraction of dose absorbed (F _abs ) was monitored as a function of time measured in Monte Carlo steps (MCS). The absorption number An was calculated from the mean intestinal transit time and the absorption rate constant adhering to each of the drugs examined. Results. A correspondence between the probability factor used to simulate drug absorption and the conventional absorption rate constant derived from the analysis of data was established. For freely soluble drugs, the estimates for F _abs derived from simulations using as an intestinal transit time 24500 MCS (equivalent to 4.5 h) were in accord with the corresponding data obtained from literature. For sparingly soluble drugs, a comparison of the normalized concentration profiles in the tube derived from the heterogeneous tube model and the classical macroscopic mass balance approach enabled the estimation of the dissolution probability factor for five drugs examined. The prediction of F _abs can be accomplished using estimates for the absorption and the dissolution probability factors. Conclusions. A fully computerized approach which describes the flow, dissolution and absorption of drug in the gastrointestinal tract in terms of probability concepts was developed. This approach can be used to predict F _abs for drugs with various solubility and permeability characteristics provided that probability factors for dissolution and absorption are available.     

Methanol Inhalation: Site and Other Factors Influencing Absorption,and an Inhalation Toxicokinetic Model for the Rat

Purpose. This investigation was conducted to identify the site and characteristics of methanol absorption and to develop an inhalation model relating methanol absorption, blood concentration, and elimination. Methods. Rats were exposed to methanol in chambers that allowed measurement of methanol uptake, ventilation, and blood concentrations; anesthetized rats with a tracheal cannula were examined to determine tracheal concentrations. In separate experiments, methanol-exposed rats received an iv methanol bolus to examine the effect of blood methanol on ventilation and absorption; ventilation also was manipulated by CO₂ or pentobarbital to assess the effect of ventilation rate on methanol absorption. These data were combined to construct a semi-physiologic model of methanol uptake. Results. Only 1–3% of inhaled methanol reached the trachea, primarily from systemic methanol partitioning into the trachea; blood methanol did not alter methanol absorption. Manipulation of ventilation and application of the pharmacokinetic model indicated that ventilation was less significant than environmental methanol concentration in determining the fraction of inhaled methanol absorbed, although both parameters were important determinants of the total mass absorbed. Conclusions. These data indicate that methanol uptake is a complex process that depends upon several parameters. Despite these complexities, a relatively simple semi-physiologic model was capable of describing methanol uptake over a wide range of exposure concentrations in the rat.