A Review of: “Statistics: Concepts and Controversies,Sixth Edition,by D. S. Moore and W. I. Notz (Eds.)”

Contrasts were evaluated for the maximum blood or plasma concentration (C _max) of drugs measured after repeated and single oral administrations. Variances C _max of were calculated and also simulated for a single drug as well as the comparison of two formulations, i.e., for the analysis of investigations of both bioavailability and bioequivalence. The coefficient of variation (C V) of C _max was higher in the steady state than after a single drug administration when the variability of the disposition rate constant (k) was substantially larger than that of the absorption rate constant (k_a )In turn, the CV of C _max was substantially lower following repeated than after single drug administration when the variability of k_a dominated that of k.The latter condition often prevails in practice since the relative variation of absorption rates generally substantially exceeds that of clearance (the latter being proportional to k) The statistical insensitivity is superimposed on the low kinetic sensitivity exhibited by C _maxfollowing repeated drug administrations. Consequently, bioequivalence trials conducted in the steady state generally permit a declaration of equivalence even between drug products that have very different absorption rates     

Physiological mechanism-based analysis of dose-dependent gastrointestinal absorption of L-carnitine in rats

We evaluated the dose-dependent (saturable) gastrointestinal absorption of L -carnitine, a lipid-lowering agent, in rats by a physiological mechanism-based approach to clarify its absorption characteristics and to examine the in vitro (in situ)–in vivo correlation in intestinal transport. The intestinal absorption rate constant (k_a), which was estimated by the analysis of gastrointestinal disposition, decreased markedly from 0.1061 to 0.0042 min⁻¹ when the dose was increased from 0.05 μmol rat⁻¹ (low dose) to 100 μmol rat⁻¹ (high dose). The dose-dependence in k_a was attributable to the saturability of intestinal transport that, in the perfused intestine, was similar to the saturability in k_a. At the high dose, the apparent absorption rate constant (k_a′) of 0.0021 min⁻¹, which was estimated by the analysis of plasma concentrations after oral administration, was an order of magnitude smaller than the gastric emptying rate constant (k_g) of 0.059 min⁻¹ and comparable with the k_a of 0.0042 min⁻¹, suggesting that the gastrointestinal absorption of L -carnitine is absorption-limited in the intestine. At the low dose, where intestinal L -carnitine absorption was far more efficient, the k_a′ of 0.0172 min⁻¹ was smaller than the k_a of 0.1061 min⁻¹ and closer to the k_g of 0.072 min⁻¹, suggesting that apparent absorption was retarded by gastric emptying which is less efficient than intestinal absorption. This shift in the rate-determining process with an increase in dose explains the less marked dose dependence in k_a′ compared with k_a. The bioavailability decreased from 100 to 42% with an increase in dose. This could be accounted for quantitatively by a reduction in the fraction absorbed (F_a,oral) due to a reduction in k_a, assuming first-order absorption during the transit time of T_si through the small intestine (F_a,oral=1−exp(−k_a · T_si)). Thus, using L -carnitine as a model, this study has successfully demonstrated that the saturability in gastrointestinal absorption can be correlated with the intestinal transport in a quantitative and mechanism-based manner. This should be of help not only for developing more efficient oral L -carnitine delivery strategies, taking advantage of in vitro (in situ) information about the intestinal transport mechanism, but also for establishing a more generally applicable in vitro (in situ)–in vivo correlation in gastrointestinal absorption. © 1998 John Wiley & Sons, Ltd.     

Calculation of the gastric absorption rate constants of 5-substituted barbiturates through theR m values or substituent ΔR m constants in reversed-phase partition chromatography

A linear correlation between the logarithm of the in situgastric absorption rate constants (k_a)of 5-substituted barbiturates and their R_m values in selected reversed-phase partition chromatographic systems is demonstrated, as well as between the log k_a and the R_m derived parameters. On the basis of the chromatographic behavior of 14 closely related compounds of this series, the substituent R_m constants for the main functional groups are calculated, so that the gastric absorption constants of nontested barbiturates can be predicted with close approximation. Predicted R_m and log k_a values show an excellent correlation with log 1/C values taken from pharmacological literature data. The migration mechanisms involved in reversed-phase partition chromatography are discussed in connection with the results obtained with other types of partition systems and with bulk-phase solvents. The possible relationships between chromatographic parameters and absorption rate constants found from absorption sites other than the stomach are outlined; as well as the advantages and limitations of the procedure.     

Time-Dependent Oral Absorption Models

The plasma concentration–time profiles following oral administration of drugs are often irregular and cannot be interpreted easily with conventional models based on first- or zero-order absorption kinetics and lag time. Six new models were developed using a time-dependent absorption rate coefficient, k_a(t), wherein the time dependency was varied to account for the dynamic processes such as changes in fluid absorption or secretion, in absorption surface area, and in motility with time, in the gastrointestinal tract. In the present study, the plasma concentration profiles of propranolol obtained in human subjects following oral dosing were analyzed using the newly derived models based on mass balance and compared with the conventional models. Nonlinear regression analysis indicated that the conventional compartment model including lag time (CLAG model) could not predict the rapid initial increase in plasma concentration after dosing and the predicted C_max values were much lower than that observed. On the other hand, all models with the time-dependent absorption rate coefficient, k_a(t), were superior to the CLAG model in predicting plasma concentration profiles. Based on Akaike's Information Criterion (AIC), the fluid absorption model without lag time (FA model) exhibited the best overall fit to the data. The two-phase model including lag time, TPLAG model was also found to be a good model judging from the values of sum of squares. This model also described the irregular profiles of plasma concentration with time and frequently predicted C_max values satisfactorily. A comparison of the absorption rate profiles also suggested that the TPLAG model is better at prediction of irregular absorption kinetics than the FA model. In conclusion, the incorporation of a time-dependent absorption rate coefficient k_a(t) allows the prediction of nonlinear absorption characteristics in a more reliable manner.     

Sensitive and Specific Determination of the Equivalence of Absorption Rates

Purpose. To develop a new method for the direct, sensitive evaluation of the equivalence of absorption rates in linear kinetic systems. Methods. Concentrations are obtained before the earlier peak. Ratios of concentrations adjusted for the corresponding ratio of AUCs (area under the curve contrasting plasma concentration with time), or their logarithm, are extrapolated by linear regression to the time of drug administration. The intercept estimates the ratio of absorption rate constants (k_a), or its logarithm. Results. The intercept metric assesses the equivalence of absorption rates with very favourable characteristics. The metric reflects the k_a-ratio specifically (i.e., not affected by other kinetic parameters), is approximately linear to it, exhibits high kinetic sensitivity and excellent statistical properties. With many observations, the intercept metric has near-ideal features, including high power for determining bioequivalence and the ability to detect a 25% difference between k_a values. With only 3 or 4 measurements before the earlier peak, the performance of the metric depends on the preset regulatory conditions. Reasonably good power is noted if the bioequivalence limits determine a 50% difference between two metrics and, approximately, between two k_a values. The intercept metric shows very high power with a wider bioequivalence range. The power declines only moderately with increasing intraindividual variation of k_a. The equivalence of absorption rates is assessed with much higher power by the intercept metric than by C_max. Conclusions. The excellent kinetic and statistical properties of the intercept metric enable the specific and sensitive determination of the equivalence of absorption rates.     

Relationship between lipophilicity and absorption from the liver surface of paraben derivatives and antipyrine in rats

Objectives The importance of drug lipophilicity on absorption from the liver surface was examined in rats using paraben derivatives, antipyrine, Sudan III, and Sudan blue. Methods The log partition coefficient (PC) of n‐octanol/water ranged from ?1.39 to 4.62. The compounds were applied to the rat liver surface using a cylindrical diffusion cell (i.d. 9 mm). Key findings The rate of absorption at 15 min was calculated to be 13.9% for paraben, much lower than that for its derivatives methylparaben, propylparaben and butylparaben (～80%). The obtained first‐order absorption rate constant (k_a) of paraben, methylparaben, propylparaben and antipyrine increased according to lipophilicity. Further lipophilicity resulted in a fall in k_a, implying the importance of affinity for lipids and water in absorption from the liver surface. Thus, a compound with a log PC of around 2.5 is considered to have maximum absorbability from the rat liver surface. A good relationship (r² = 0.97) was recognized between the log k_a and log reciprocal value with the square root of molecular weight of the compounds with a log PC below 2.5. Conclusions The rate of absorption of a drug from the liver surface could be estimated from physicochemical properties such as lipophilicity and molecular weight.     

药物吸收速率常数的一种简便计算法

本文提出了一种计算药物吸收速率常数k_a的简便算法。该法利用血药浓度-时间曲线的特征值(峰值C_max、达峰时t_m及转折值c₁)来直接计算k_a。计算公式如下:式中K为药物消除速率常数。理论上,对于一室开放形模型,按(1)式计算k_a是精确的;对于二室模型则仅提供k_a的一个初步估计。实践上,按(1)式计算k_a,其精确程度不仅依赖于所用的模型,而且依赖于该式中所含的各个参数的估计。     

对计算药物吸收速率常数的Wagner-Nelson法的一点改进

在口服(或其他静脉外途径,下同)给药的情况下,多数药物的体内过程显示一室开放形模型(图1)的特征,计算所给药物未经变化而到达体循环的速率——吸收速率(一般用一级速率常数K_α表征),最常用的方法是Wagne-Nelson法。     

Intestinal absorption-partition relationships: A tentative functional nonlinear model

Models and equations designed to elucidate passive intestinal absorption mechanisms by analysis of the relationship between the absorption rate constant (k_a)and either the partition coefficients (P)or a related partition constant for homologous series of substances, are reviewed. Classical nonlinear physical models, such as those which assume the existence of a nonstirred layer or equilibrium extraction, predict sigmoidal or hyperbolic relationships between k_a and P,whereas other models, which regard the membrane as a heterogeneous multicompartment system, predict parabolic or bilinear relationships between log k_a and log P.In the present paper, an alternative model is proposed, which incorporates the Wagner-Sedman equilibrium extraction model together with the existence of pores, which play a fundamental role for compounds below 250in molecular weight. Several apparently contradictory absorption-partition literature data are shown to be highly consistent with the tentative model proposed.     

Insulin Self-association: Effects on Lung Disposition Kinetics in the Airways of the Isolated Perfused Rat Lung (IPRL)

Purpose To characterize the kinetic dependence of pulmonary absorption and metabolism of insulin and lispro on the magnitude of their hexameric association. Methods Hexamer content by weight percent (%Hex) in various insulin-zinc and lispro-zinc solutions were determined by quantitative centrifugal ultrafiltration and zinc titration with terpyridine (QCUF-ZTT). Each of the solutions (0.1 ml) was then administered into the airways of the IPRL of normal and experimental diabetic animals. Rate constants were determined for lung absorption (k _a) and non-absorptive loss (k _nal; comprising mucociliary clearance and metabolism). Results %Hex in administered solutions ranged from 3.3 to 94.4%. Data analysis showed excellent correlations between the values for k _a or k _nal and %Hex, irrespective of insulin type, concentration, solution pH or ionic strength. The values for k _a decreased (0.22 → 0.05 h⁻¹) with increasing %Hex, as did values for k _nal. At %Hex in administered solutions ≥50%, values for k _nal approached estimates for the rate constant for mucociliary clearance, implying that lung metabolism occurred primarily with monomeric insulin. There were no differences in insulin disposition kinetics between lungs taken from experimental diabetic and sham-control animals. Conclusions The kinetics of pulmonary insulin disposition depended on the magnitude of molecular self-association. Dissociated forms of insulin (dimers or monomers) in the dosing solution showed higher rates than hexamers for both lung absorption and metabolism.     

pH-Related Changes in the Absorption of Dipyridamole in the Elderly

The bioavailability of dipyridamole, a poorly soluble weak base, was evaluated in 11 healthy, older subjects (65 years), 6 with a low fasting gastric pH (control) and 5 with a fasting gastric pH > 5 (achlorhydric), in a randomized, crossover design. Subjects received 50 mg dipyridamole as a single oral dose both with and without pretreatment with 40 mg famotidine (control subjects) or 1360 mg glutamic acid HC1 (achlorhydric subjects). Gastric pH was monitored by Heidelberg radiotelemetric capsule. Gastric emptying of ^99mTc-radiolabeled orange juice was measured. Gastric pH appeared to be a primary determinant in dipyridamole absorption in the elderly. Elevated gastric pH resulted in compromised dipyridamole absorption compared to low-gastric pH conditions in all cases. The administration of glutamic acid hydrochloride to achlorhydric subjects prior to the dose of dipyridamole corrected for the decreased C _max and AUC(0–36) exhibited in achlorhydric subjects without pretreatment. T_max and k _a were slower in achlorhydrics, although pretreatment with glutamic acid HC1 tended to normalize these parameters. Based on these results, it would be beneficial for achlorhydrics to take glutamic acid hydrochloride prior to taking dipyridamole and other medications which need a low gastric pH for complete absorption. The administration of 40 mg famotidine was successful in elevating the gastric pH to >5 in all subjects and maintained it at >5 for at least 3 hr in all subjects tested. The lack of differences in C _max and AUC(0–36) with significant differences in T _max and k _a indicated that control subjects after treatment with famotidine may serve as an adequate model for achlorhydrics with respect to the extent of absorption, but not with respect to the rate of absorption. Gastric emptying of a nutrient liquid was significantly slower in achlorhydric subjects than in control subjects. Finally, fasting serum gastrin appeared to be a relatively reliable and easy method for screening for achlorhydria in the elderly.     

Pharmacokinetic study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma

K027 [1‐(4‐hydroxyiminomethylpyridinium)‐3‐(4‐carbamoylpyridinium)–propane dibromide] is a promising new reactivator of organophosphate‐ or organophosphonate‐inhibited acetylcholinesterase (AChE) with low acute toxicity and broad spectrum efficacy. The aim of the present study was to compare the pharmacokinetics of both compounds. Male Wistar rats (body weight = 320 ± 10 g) were administered a single intramuscular dose of K027 (22.07 mg kg^?1) and an equimolar dose of trimedoxime. Blood was collected at various time intervals until 180 min. Plasma samples were analyzed by reversed‐phase HPLC with ultraviolet (UV) detection. The recovery of both oximes from the plasma was approximately 90% and a linear relationship (R² > 0.998) was observed between the peak areas and concentrations of calibrated standards in the range 1–100 µg ml^?1. Near‐identical plasma profiles were obtained for both compounds. No differences were found in the mean ± SD values of C_max (18.6 ± 2.5 vs 20.0 ± 6.3 µg ml^?1, P = 0.72) and AUC_0–180min (2290 ± 304 vs 2269 ± 197 min µg ml^?1, P = 0.84). However, the percentage coefficient of variation of the first‐order rate constant of absorption (k_a) was 3‐fold higher (P < 0.01) providing evidence for more erratic absorption of intramuscular trimedoxime as compared with K027. In conclusion, oxime K027 might have superior pK properties that may be translated in its faster absorption and subsequent tissue distribution. Copyright © 2011 John Wiley & Sons, Ltd.     

Application of the Loo-Riegelman absorption method

The Loo-Riegelman absorption method provides the correct A/V₁ value and the correct rate constant k_a (if absorption is first order), whether metabolism occurs in compartment 1 only, compartment 2 only, or both compartments 1 and 2 of the two-compartment open model. In cases where there is metabolism in compartment 2, the disposition parameters estimated from intravenous data are only apparent and not the real values. The correct A/V₁ and k_a values are obtained, however, only under conditions not hithertofore specified. These conditions are that there must be essentially no bias in the disposition parameters k₁₂, k₂₁, and k_el. and in the C₀ value estimated from the intravenous data, and that in the oral study a large number of interpolated plasma concentrations, as well as the observed plasma concentrations, must be used, especially for drugs with long half-lives. It is shown that application of the Guggenheim method to the initial A₁ V₁, tvalues frequently provides a better method of estimating A/V₁ and k_a than the classical method. If biased disposition parameters are used in application of the Loo-Riegelman method to oral data, then essentially the correct value of k_a will be estimated, but the estimate of A/V₁ will be approximately equal to the true value of A/V₁ multiplied by the ratio of the biased C₀ value (obtained in fitting the intravenous data) to the true C₀ value of the intravenous data. The above indicates that intravenous data should be fitted by computer until there are no systematic deviations or trends and as small a sum of squared deviations as possible is obtained. The oral data should be fitted by spline or Akima methods, or similar procedures, to produce a function which passes through each observed plasma concentration and at the same time provides a large number of interpolated concentration data.Partly supported by Public Health Service Grant 5-P11-GM15559.     

Physicochemical characteristics and gastrointestinal absorption behaviors of S-propargyl-cysteine,a potential new drug candidate for cardiovascular protection and antitumor treatment

Abstract

1. As a potential new drug candidate for cardiovascular protection and antitumor treatment, the physicochemical properties, gastrointestinal (GI) absorption behaviors and mechanisms of S-propargyl-cysteine (SPRC) were investigated in this study.

2. SPRC exhibited favorable solubility in aqueous media. The log P and log D values were low (≤1.93?±?0.08). The pK_a in the acidic and basic regions was 2.08?±?0.02 and 8.72?±?0.03, respectively. The isoelectric point was 5.40?±?0.02. SPRC was stable in the rat GI fluids, and showed no obvious adsorption and metabolism in the rat GI tract.

3. SPRC displayed poor gastric absorption and favorable intestinal absorption in the rat in situ GI perfusion model. Absorption rate constants (k_a), hourly absorption percentage (P) and apparent permeability coefficient (P_app) of SPRC in the small intestine were ≥0.77?±?0.06?h^?1, 59.25?±?4.02% and (7.99?±?0.88)?×?10^?5?cm/s, respectively. Absorption of SPRC exhibited a certain dependence on physiological pH and absorption region. Absorption of SPRC was not inhibited by l-methionine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid.

4. SPRC showed favorable oral absorption. It can be categorized as a BCS class I drug. The membrane pore transport appeared to be one of the predominant absorption modes for SPRC.     

Effects of bladder resorption on pharmacokinetic data analysis

In modern pharmacokinetic analysis, the urinary bladder is usually viewed as a nonreturning compartment or storage site for renally excreted compounds. Our previous studies have indicated appreciable bladder resorption of drugs. The present study used computer simulations to evaluate the quantitative importance of several potential determinants of bladder resorption, namely the bladder resorption rate constant (k _a), interval between bladder voiding (Δt _void),ratio of renal elimination rate constant to overall elimination rate constant (k _ex:k _el ratio), andk _el ort _1/2. The data identifiedk _a, Δt _void, andk _ex:k _el ratio as the three most important determinants of the rate and extent of bladder resorption. We further examined the errors introduced in the derived pharmacokinetic parameters due to omission of bladder resorption. Plasma concentration-time profiles and urinary excretion-time profiles were generated by simulations using different values ofk _a, Δt _void, andk _ex:k _el ratio. These profiles were used to derive the pharmacokinetic parameters, including the renal clearance (CL _renal), total body clearance (CL _total), nonrenal clearance (CL _nonrenal),t _1/2, mean residence time (MRT), amount and fraction of dose excreted in urine (A _ex andf _e), and volume of distribution at steady state (Vd _ss). Data show that resorption of drug from the bladder into the systemic circulation increased the area under the plama concentration-time profile,MRT andt _1/2, but decreasedCL _renal,CL _total,A _ex, andf _e.Vd _ss was relatively unchanged. Overestimation of MRT andt _1/2 was dependent onk _a,k _ex:k _el ratio,and Δt _void. Underestimation inCL _renal,A _ex, andf _e was not dependent on thek _ex:k _el ratio, but was affected by changes ink _a and Δt _void.CL _renal andf _e were the most sensitive pharmacokinetic parameters, with a≥50% underestimation at ak _a value that we reported previously, for the bladder absorption of antipyrine in rats with intact urothelium. In summary, these data indicate (i) alteration in the plasma concentration-time profiles and urinary excretion-time profiles due to bladder resorption, and (ii) substantial over-or underestimation in the derived pharmacokinetic parameters due to erroneous omission of bladder resorption. Supported in part by MERIT grant R37 CA-49816, and Research Career Development Award K04 CA-01497 for J. L-S. Au, from The National Cancer Institute, National Institutes of Health, Department of Health and Human Services.     

Non-linear mixed effect modeling of the time-variant disposition of erythropoietin in anemic cancer patients

Chemotherapy‐induced anemia is a frequent complication in cancer treatment. The aim was to develop a pharmacokinetic (PK) model that describes the time‐dependent decline of epoetin alfa (rHuEPO) clearance following thrice (t.i.w.) or once (q.w.) weekly subcutaneous injections in cancer patients using a population PK approach. Serum concentrations of rHuEPO were available retrospectively from a phase I study. A one‐compartment model with first‐order elimination described rHuEPO PK. Sequential zero‐ and first‐order (k_a) processes with duration (t_lag) characterized the absorption. Population PK analysis was performed using NONMEM. The influence of several covariates was tested. Model evaluation was performed using visual predictive check. Precision of parameter estimates was assessed by standard errors and confidence intervals determined by bootstrap analysis. Apparent clearance (CL/F) and volume of distribution (V_c/F) were 25.6% lower and 29.2% higher for q.w. than t.i.w. groups. RHuEPO was absorbed for 10% during 24.6 h through the zero‐order process. Following which 90% of the dose was absorbed through the first‐order process with k_a of 0.033 h^?1. The most significant covariates were the time‐dependent decrease of CL/F with an increase in body weight, a decrease in reticulocyte count, a decrease in hemoglobin baseline, an increase in total number of chemotherapy cycles, and platinum‐containing chemotherapy. AGE served as an important covariate on FRAC and k_a. Visual predictive check showed no deviation from observed values. The PK model adequately predicted rHuEPO concentration‐profiles in all individuals. Relevant covariates were identified and incorporated into the model. Copyright © 2010 John Wiley & Sons, Ltd.     

A MODEL BASED ASSESSMENT OF REDISTRIBUTION DEPENDENT ELIMINATION AND BIOAVAILABILITY OF RIFABUTIN

The autoinduction characteristic of rifabutin (RIF) following multiple oral dosing was investigated via pharmacokinetic modeling. A two-compartment model with first-order absorption was fit to plasma RIF data obtained from a study conducted in healthy normal volunteers following both a single and multiple oral doses. Parameter estimates showed an elimination rate constant (k₁₀) of about 0·12--0·14 h⁻¹ which was independent of the single or multiple-dosing condition. The lower-than-expected drug accumulation following multiple dosing seems to suggest that prolonged dosing perturbs the linear kinetic system. However, this analysis has shown no significant changes (p>0·05) in the rate constants describing RIF absorption, tissue distribution/redistribution, and elimination. The mean rate of drug redistribution from the tissue compartment (k₂₁; 0·04--0·06 h⁻¹) was twofold to threefold lower than k₁₀, and, with a large steady-state distribution volume (V_ss/F after a single dose, 1630 L), RIF elimination appears to be dependent on drug redistribution. This hypothesis was further supported by a significant correlation (p<0·01) BETWEEN RIF TISSUE REDISTRIBUTION (k₂₁) and terminal disposition phase rate (λ_z) constants. The redistribution dependent elimination of RIF also helps explain the stability of the terminal half-life under both single and multiple-dosing paradigms. Urinary excretion of RIF and its 25-O-deacetyl metabolite totalled less than 7% of the oral dose following single dosing, and decreased to about 4% after multiple dosing. For individual patients, the decrease in urinary recovery of the 25-O-deacetyl metabolite was directly proportional to the decrease in urinary RIF recovery. In addition, both estimates of the model intercepts (A and B) were lower following multiple dosing. Further analyses revealed a linear relationship between A and B intercepts, and also between the urinary RIF recovery and the B intercept. These relationships, in conjunction with the lack of significant increase in the rate of elimination, indicate that induction of presystemic extrahepatic metabolism and/or decrease in the extent of oral absorption may be the primary causes for the lower-than-expected systemic RIF plasma levels after multiple oral dosing.     

Mean residence time for drugs subject to enterohepatic cycling

A physiologically realistic model of enterohepatic cycling (EHC) which includes separate liver and gallbladder compartments, discontinuous gallbladder emptying and first-order absorption from both an oral formulation and secreted bile (k_a ^po and k_a ^b, respectively) has been developed. The effect of EHC on area under the first-moment curve (AUMC) of drug concentration in plasma and on parameters derived from the AUMC was investigated. Unlike AUC, AUMC is dependent on the time and time-course of gallbladder emptying, increasing as the interval between gallbladder emptying increases. Consequently, mean residence time (MRT) is also a time-dependent parameter. Analytical solutions for MRT^iv and MRT^po were derived. Mean absorption time (MAT = MRT^po — MRT^ivj is also time-dependent, contrary to findings previously published for a model of EHC with a continuous time lag. MAT is also dependent on k _a ^po , k _a ^b and the hepatic extraction ratio. The difference between MRT _po ^s two formulations with unequal k _a ^po values may deviate from the difference in the inverse of their absorption rate constants. Implications for design and interpretation of pharmacokinetic studies include (i) MAT values may be dominated by the time-course of recycling rather than the time-course of the initial absorption, depending on the extent of EHC and (ii) the unpredictable nature of the time of gallbladder emptying will contribute to intrasubject variability in derived parameters during crossover studies. Knowledge of the extent of EHC is invaluable in deciding whether modification of the in vitro release characteristics of an oral formulation will have any effect on the overall time-course of absorption in vivo. Techniques to monitor or control gallbladder emptying may be helpful for reducing variability in pharmaco-kinetic studies for compounds which are extensively cycled in bile.     

Prediction of drug-drug interaction during oral absorption of carrier-mediated compounds in humans

A microscopic mass balance approach has been developed to estimate the extent and rate of absorption for carrier-mediated compounds. For the case of the competitive inhibition in the presence of an inhibitor which shares the same carrier, the fraction dose absorbed (F) and absorption rate constant (k_a) of a drug can be calculated from its concentration profile in the intestinal lumen. Absorption parameters obtained by single-pass perfusion experiments were used in the simulation of the absorption of some aminopenicillins. Predicted fractions dose absorbed and absorption rate constants of ampicillin and amoxicillin were significantly reduced in the presence of a 6-times higher molar dose of cyclacillin. The drug-drug interactions on the competitive absorption of carrier-mediated compounds were determined with regard to F and k_a. Predicted decreases in F for some aminopenicillins correlated well with decreases in the urinary recovery in humans reported in the literature. Predicted decreases in the mean absorption rate constant explain the delays in the time of peak plasma concentration (T_max) reported in humans.