The ratio of first to zeroth moments of the plasma profile of an oral drug undergoing first-pass and linear reversible metabolism

Based on the convolution integral, equations have been drived for the ratio of the first to the zeroth moments of the plasma concentration—time curve (AUMC/AUC) parameters for a drug (p) undergoing first-pass and reversible metabolism and its reversible metabolite (m). According to these equations, the AUMC/AUC of a drug administered orally and of its reversible metabolite can be related to the mean absorption times, the ratios of the fraction of the dose entering the systemic circulation to the bioavailability, the first-time fractional conversion of each compound, and the AUMC/AUC ratios after intravenous administration of each compound. The proposed approach allows a more generalized derivation method for AUMC/AUC of a drug administered orally and undergoing first-pass and reversible metabolism. It is also applicable to any other extravascular route.     

Primary,secondary, and tertiary metabolite kinetics

Because of the propensity of nascently formed metabolites towards sequential metabolism within formation organs, theoretical and experimental treatments that achieve mass conservation must recognize the various sources contributing to primary, secondary, and tertiary metabolite formation. A simple one-compartment open model, with first-order conditions and the liver as the only organ of drug disappearance and metabolite formation, was used to illustrate the metabolism of a drug to its primary, secondary, and tertiary metabolites, encompassing the cascading effects of sequential metabolism. The concentration-time profiles of the drug and metabolites were examined for two routes of drug administration, oral and intravenous. Formation of the primary metabolite from drug in the gut lumen, with or without further absorption, and metabolite formation arising from first-pass metabolism of the drug and the primary metabolite during oral absorption were considered. Mass balance equations, incorporating modifications of the various absorption and conversion rate constants, were integrated to provide the explicit solutions. Simulations, with and without consideration of the sources of metabolite formation other than from its immediate precursor, were used to illustrate the expected differences in circulating metabolite concentrations. However, a simple relationship between the area under the curve of any metabolite, M,or [AUC{m}],its clearance [CL{m}],and route of drug administration was found. The drug dose, route, fraction absorbed into the portal circulation, F_abc,fraction available of drug from the liver, F,availabilities of the metabolites F{m}from formation organs, and CL{m}are determinants of the AUC{m}'s.After iv drug dosing, the area of any intermediary metabolites is determined by the iv drug dose divided by the (CL{m}/F{m})of that metabolite. When a terminal metabolite is not metabolized,its area under the curve becomes the iv dose of drug divided by the clearance of the terminal metabolite since the available fraction for this metabolite is unity. Similarly, after oral drug administration, when loss of drug in the gut lumen does not contribute to the appearance of metabolites systemically, the general solution for AUC{m} isthe product of F_abc and oral drug dose divided by [CL{m}/F{m}].A comparison of the area ratios of any metabolite after po and iv drug dosing, therefore, furnishes F_abc.When this fraction is divided into the overall systemic availability or F_sys,the drug availability from the first-pass organs, F,may be found. The potential application of these relationships to other schemes, namely, drugs that have competing metabolic pathways within the liver and/or intestine as well as reversible metabolism is briefly discussed.In view of the various contributing sources of metabolite formation, and the modulation of circulating metabolite concentrations by sequential first-pass metabolism of the metabolite, caution is given against the use of area ratios of metabolite after iv drug and metabolite administration for estimations of metabolite formation clearances.This work was supported by the Medical Research Council of Canada (MA-9104 and MA-9765) and the NIH (GM-38250). KSP is a recipient of the Faculty Development Award from MRC, Canada.     

Application of Mean Residence-Time Concepts to Pharmacokinetic Systems with Noninstantaneous Input and Nonlinear Elimination

Equations describing the mean residence time (MRT) of drugs in the body are derived for drugs that are administered by first-and zero-order rates into systems with Michaelis–Menten elimination. With computer simulations, the validity of these equations, the differences between them, and the conventional approach using the AUMC/AUC or the summation of mean times are demonstrated by examining calculations of the percentage of the administered dose eliminated at the MRT and AUMC/AUC. The effects of the absorption rate on the AUC and on the approximate and true MRT values in a nonlinear pharmacokinetic system are also illustrated with computer simulations. It was previously found that the true MRT_iv = V _ss · AUC_iv/dose for an iv bolus. The total MRT (sum of input and disposition) of a drug after noninstantaneous administration was found to be a function of the MRT_iv, two values of AUC (iv and non-iv), and exactly how the drug is administered expressed as the mean absorption time (MAT). In addition, a theoretical basis is proposed for calculation of the bioavailability of drugs in both linear and nonlinear pharmacokinetic systems.     

A method for calculating the mean absorption time of drugs undergoing reversible and first-pass metabolism

A method has been derived for calculating the mean absorption time of an oral drug and its interconversion metabolite which is generated from the drug systemically and presystemically. The method evolves from the convolution integral and requires plasma AUC and AUMC values after separate intravenous administration of the drug and its interconversion metabolite and oral administration of the drug. It can also be used to calculate the mean input time of a drug undergoing reversible metabolism and administered by any other extravascular route. Results of a simulation study using both errorless and errant data indicate that, when the absorption rate constant of a drug or its interconversion metabolite is not much larger than the apparent elimination rate constant, the proposed method performs satisfactorily. However, when the absorption rate constant of a drug or its interconversion metabolite is much larger than the apparent elimination rate constant, the proposed method appears to be inaccurate.     

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.     

The determination of mean residence time using statistical moments:It is correct

The present communication seeks to end a controversy created by a recent publication regarding the applicability of statistical moment principles for determination of mean residence time of drug in the body ¯t_b.It is shown that the equation ¯t_b=AUMC/AUC iscorrect when applied to pharmacokinetic systems in which the total drug elimination rate is directly proportional to the drug concentration in the systemic circulation, i.e., firstorder central elimination. More general equations for ¯t_b in terms of elimination rate, amount eliminated, and amount in the body are presented along with demonstrations of their utility.     

Pharmacokinetics of a new reversible proton pump inhibitor,YH1885, after intravenous and oral administrations to rats and dogs: hepatic first-pass effect in rats

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5–20 mg kg⁻¹, to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50–200 mg kg⁻¹, to rats, the area under the plasma concentration–time curve from time zero to 12 or 24 h (AUC_{0–12 h} or AUC_{0–24 h}) was proportional to the oral dose of the drug, 50–100 mg kg⁻¹, however, the AUC_{0–24 h} value at 200 mg kg⁻¹ increased with less proportion to the dose increase (324, 689, and 815 μg · min mL⁻¹ for 50, 100, and 200 mg kg⁻¹, respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg⁻¹, respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg⁻¹. The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg⁻¹, was approximately 70% (116 versus 163 μg · min mL⁻¹) of that after iv administration of the drug, 5 mg kg⁻¹, to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5–20 mg kg⁻¹, to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg⁻¹, to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5–20 mg kg⁻¹, to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC_{0–10 h} values were not significantly different (96.8 versus 98.2 μg · min mL⁻¹) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs. Copyright © 1998 John Wiley & Sons, Ltd.     

Effects of First-Pass Metabolism on Metabolite Mean Residence Time Determination After Oral Administration of Parent Drug

Metabolite kinetics after oral drug administration can be determined, without separate metabolite administration, using the concepts of mean residence time (MRT). The MRT of parent drug and metabolite after oral administration of the parent drug, MRTp,p(oral) and MRTm,p(oral), can be calculated directly from the drug and metabolite profiles. The difference between MRTm,p(oral) and MRTp,p(oral), termed Delta MRT, yields an estimate of MRT of metabolite when the metabolite is given as an iv bolus, MRTm,m(iv). The calculation is simple for drugs that are known to undergo negligible first-pass metabolism. Correction can also be made when extent of first-pass metabolism is known. Ambiguity is encountered, however, when the degree of first-pass metabolism is unknown. When the delta MRT is negative, then first-pass metabolism must be considered. A positive value of delta MRT, on the other hand, is not a definitive indication of the absence of first-pass metabolism. It may occur in the presence or absence of first-pass metabolism. Ignoring the possibility of first-pass metabolism when a positive value of delta MRT occurs may lead to an incorrect estimate of MRTm, m(iv). The estimation error is relatively small, however, when MRTm,m(iv) MRTp,p(iv), even when first-pass metabolism is extensive. This situation may apply to the administration of a prodrug.     

Physiological Modeling to Understand the Impact of Enzymes and Transporters on Drug and Metabolite Data and Bioavailability Estimates

Purpose

To obtain mathematical solutions that correlate drug and metabolite exposure and systemic bioavailability (F _sys) with physiological determinants, transporters and enzymes.

Methods

A series of physiologically-based pharmacokinetic (PBPK) models that included renal excretion and sequential metabolism within the intestine and/or liver as metabolite formation organs were developed. The area under the curve for drug (AUC) and formed metabolite (AUC{mi,P}) were solved by matrix inversion.

Results

The PBPK models revealed that AUC{mi,P} was dependent on dispositional parameters (transport and elimination) for the drug and metabolite. The solution was unique for each metabolite formation organ and was dependent on the type of drug and metabolite elimination organs. The AUC ratio of the formed metabolite after oral and intravenous drug dosing was useful for determination of the fraction absorbed (F _abs) and not the systemic bioavailability (F _sys) when either intestine or liver was the only drug elimination organ.

Conclusions

The AUC ratio of the formed metabolite after oral and intravenous drug dosing differed from that for drug and would not provide F _sys. However, the AUC ratio of the formed metabolite for oral and intravenous drug dosing furnished the estimate of F _abs when intestine or liver was the only drug metabolic organ.     

Bioavailability of dextromethorphan (as dextrorphan) from sustained release formulations in the presence of guaifenesin in human volunteers

A multiple dose bioavailability study with six healthy male human volunteers was conducted. The bioavailability of an experimental sustained release tablet containing dextromethorphan hydrobromide (DXP-HBr), was compared with a marketed sustained release DXP-HBr suspension in a three-way crossover study. Plasma samples, collected serially after oral drug administration, were analysed for the major metabolite of dextromethorphan (DXP), dextrorphan (DX), using a specific HPLC method with fluorescence detection. The bioavailability parameters; area under the concentration–time curve (AUC), maximum plasma concentration (C_max), and time to peak (T_max), were obtained from the plasma concentration–time data. Additionally, pharmacokinetic parameters such as mean residence time (MRT), accumulation factor (R), fluctuation index (F_i), total body clearance (Cl), and the average concentration (C ¯) were estimated by using model independent kinetics approach. Analysis of variance of the data revealed that the presence of guaifenesin in the test formulation does not appear to have a statistically significant (p >0.05) effect on the bioavailability of dextromethorphan as dextrorphan. The relative bioavailability of the tablet dosage form with respect to the suspension was found to be 113% on Day 1 and 110% on Day 6. Copyright © 1998 John Wiley & Sons, Ltd.     

Liver and Gastrointestinal First-pass Effects of Azosemide in Rats

Since considerable first-pass effects of azosemide have been reported after oral administration of the drug to rats and man, first-pass effects of azosemide were evaluated after intravenous, intraportal and oral administration, and intraduodenal instillation of the drug, to rats. The total body clearances of azosemide after intravenous (5 mg kg^?) and intraportal (5 and 10 mg kg^?) administration of the drug to rats were considerably smaller than the cardiac output of rats suggesting that the lung or heart first-pass effect (or both) of azosemide after oral administration of the drug to rats was negligible. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) after intraportal administration (5 mg kg^?) of the drug was significantly lower than that after intravenous administration (5 mg kg^?) of the drug (1000 vs 1270 μg min mL^?) suggesting that the liver first-pass effect of azosemide was approximately 20% in rats. The AUC from time 0 to 8 h (AUC_{0–8 h}) after oral administration (5 mg kg^?) of the drug was considerably smaller than that after intraportal administration (5 mg kg^?) of the drug (271 vs 1580 μg min mL^?) suggesting that there are considerable gastrointestinal first-pass effects of azosemide after oral administration of azosemide to rats. Although the AUC_{0–8 h} after oral administration (5 mg kg^?) of azosemide was approximately 15% lower than that after intraduodenal instillation (5 mg kg^?) of the drug (271 vs 320 μg min mL^?), the difference was not significant, suggesting that the gastric first-pass effect of azosemide was not considerable in rats. Azosemide was stable in human gastric juices and pH solutions ranging from 2 to 13. Almost complete absorption of azosemide from whole gastrointestinal tract was observed after oral administration of the drug to rats. The above data indicated that most of the orally administered azosemide disappeared (mainly due to metabolism) following intestinal first-pass in rats.     

Pharmacokinetics of verproside after intravenous and oral administration in rats

Verproside, a catalpol derivative iridoid glucoside isolated from Pseudolysimachion longifolium, is a candidate for anti-asthmatic drug. The dose-dependency of the pharmacokinetics of verproside was evaluated in rats after intravenous and oral administration. After intravenous administration of verproside (2, 5 and 10 mg/kg doses), the systemic clearance (Cl) was significantly reduced and AUC was significantly increased at 10 mg/kg dose compared to 2 and 5 mg/kg doses. The volume of distribution at steady state (V _ss) remained unchanged as the dose was increased. The extent of urinary excretion was low for both intravenous (3.3–6.2%) and oral (0.01–0.04%) doses. Isovanilloylcatalpol was identified as a metabolite after intravenous administration of verproside and showed the significant decreases in AUC and C _max at 10 mg/kg verproside dose. The reduced systemic clearance of verproside at high doses appears to be due to the saturable metabolism. Upon oral administration of verproside (20, 50 and 100 mg/kg doses), C _max was nonlinearly increased. The extent of verproside recovered from the gastrointestinal tract at 24 h after oral administration was 0.01–0.72% for all three doses studied. The absolute oral bioavailability (F) was 0.3 and 0.5% for 50 and 100 mg/kg doses, respectively. Low F appears to be due to first-pass metabolism.     

The effect of caffeine on the pharmacokinetics of acetaminophen in man

The influence of caffeine (60 mg) was studied on the pharmacokinetic characteristics of acetaminophen (500 mg single dose) in ten healthy male human volunteers in a complete cross-over design. A high-performance liquid chromatography (HPLC) method was used to analyse serum drug concentrations. Caffeine caused a highly significant (p < 0.01) increase in AUC and AUMC, a significant (p < 0.05) increase in C_max, and a significant (p < 0.05) decrease in clearance (Cl/F) of acetaminophen. We conclude that caffeine taken in doses commonly available commercially or in a cup of coffee can significantly potentiate the therapeutic potential of acetaminophen in man.     

Dose dependent pharmacokinetics of albendazole in human

Pharmacokinetics of albendazole sulphoxide (ABZ-SO) in three different single oral doses of albendazole (ABZ) (400, 800 and 1200 mg) was studied in 10 healthy human volunteers in a double blind three-way crossover design. The serum levels of albendazole main metabolite, albendazole sulphoxide (ABZ-SO), were analysed by a modified high-pressure liquid chromatography method. (ABZ is not detectable in biological fluids itself.)For ABZ-SO, there was no significant difference in the biological half life, normalized serum peak concentration (C(max-ABZ-SO)/Dose(ABZ)), time to reach peak concentration (T(max)) and mean residence time (MRT), whereas apparent clearance (Cl(p)/F), apparent distribution volume (V(d)/F), normalized area under the serum concentration-time curve (AUC(ABZ-SO)/Dose(ABZ)) and normalized area under the first moment curve (AUMC(ABZ-SO)/Dose(ABZ)) of albendazole main metabolite (ABZ-SO) were statistically different at different doses of the parent drug, resulting in substantially lower serum concentration and thereafter AUC(ABZ-SO)/Dose(ABZ) and AUMC(ABZ-SO)/Dose(ABZ) in higher doses. These observations indicate dose dependent pharmacokinetics of albendazole (observed for ABZ-SO), which were explained on the basis of a change in fraction of dose absorbed (F) as a result of slow and incomplete dissolution of the main drug in the GI tract.     

Influence of dose and route of administration on the kinetics of fluoxetine and its metabolite norfluoxetine in the rat

Fluoxetine (FL) is being used in neuropharmacology as a tool for studying various functional roles of serotoninergic neurons. Its kinetics was studied in rats, a species widely used in neurochemical studies, after IV (2.5–10 mg/kg) and oral (5–20 mg/kg) administration. When injected IV the drug followed apparent first-order kinetics up the 10 mg/kg dose. Its volume of distribution was large and total body clearance was relatively high compared to liver blood flow. The mean elimination half-lives (t _1/2) of FL and its active metabolite norfluoxetine (NFL) were about 5 and 15 h, respectively. The mean blood:plasma concentration ratios of FL and NFL approached unity and plasma protein binding was 85–90% for both compounds. After oral doses the kinetics of FL were complex. At the lowest dose tested (5 mg/kg) the drug was efficiently extracted by the liver (extraction ratio about 60%), resulting in bioavailability of only about 38%. Plasma areas under the curve (AUC) of the metabolite were approximately the same as after IV injection of the same dose; consequently the metabolite-to-parent drug ratio after oral administration (about 5) was approximately twice that after IV injection of FL (about 2.5). At higher doses, however, the oral bioavailability (e.g.C _max and AUC) appeared greater than expected, possibly because of transient saturation of FL first-pass metabolism in the case of the 10 mg/kg dose and concomitant saturation of elimination kinetics at the higher dose (20 mg/kg). The apparent eliminationt _1/2 of FL markedly increased and the metabolite-to-parent drug ratio declined with the higher dose, this also being consistent with saturable elimination. Brain concentrations reflected the plasma kinetics of FL and NFL and the metabolite-to-parent drug ratio varied with dose and time of administration and was modified at the highest dose tested. FL and its metabolite NFL distributed almost evenly in discrete brain areas and subcellular distribution was similar for both compounds. Neurochemical studies of FL should consider the formation of the active metabolite NFL and extrapolation of data across animal species requires consideration of dose dependence in the rat.     

Partial avoidance of first-pass elimination of azathioprine in rats by rectal dosing

Avoidance of the hepatic first-pass elimination of an immunosuppressive drug, azathioprine (AZ), was attempted by rectal administration of AZ in rats. The mean AUC values obtained following i.v., oral and rectal dosing of AZ to three groups of rats are 103.8 ± 22.8 (S.E.), 14.3 ± 2.45 and 60.4 ± 8.27 μg · $\text{min}\text{ml}$, respectively. The mean systemic availabilities of AZ following oral and rectal administration expressed as the ratios of the AUCs are, f_oral = 13.9% and F_rectal = 58.3% respectively. The data showed that substantial avoidance of the hepatic first-pass elimination of AZ can be achieved via rectal administration. The fraction of AZ avoided the hepatic first-pass elimination after rectal administration is discussed with respect to the pharmacokinetics of AZ in rats by means of a circulatory transport analysis.     

Pharmacokinetics and first-pass effects of liquiritigenin in rats: low bioavailability is primarily due to extensive gastrointestinal first-pass effect

1. Pharmacokinetics of liquiritigenin, a candidate for inflammatory liver disease, and its two glucuronide conjugates, M1 and M2, were evaluated in rats. The hepatic and gastrointestinal first-pass effects of liquiritigenin were also evaluated in rats.

2. After oral administration of liquiritigenin at a dose of 20?mg kg^?1, 1.07% of the dose was not absorbed from the gastrointestinal tract up to 24?h, and the F-value was only 6.68%. In vitro metabolism of liquiritigenin in S9 fractions of rat tissues showed that the liver and intestine were major tissues responsible for glucuronidation of liquiritigenin. The hepatic and gastrointestinal first-pass effects of liquiritigenin were approximately 3.67% and 92.5% of the oral dose, respectively.

3. Although the hepatic first-pass effect of liquiritigenin after absorption into the portal vein was 57.1%, the value was only 3.67% of the oral dose due to extensive gastrointestinal first-pass effect in rats. Therefore, the low F-value of liquiritigenin in rats was primarily attributable to an extensive gastrointestinal first-pass effect although liquiritigenin was well absorbed. Compared with rats, the higher F-value of liquiritigenin could be expected in humans.

     

Effect of gender in the disposition of albendazole metabolites in humans

The pharmacokinetics of albendazole in different single oral doses (400 mg, 800 mg & 1200 mg) was studied and compared in healthy male and female human volunteers using a double-blind design. The serum levels of albendazole main metabolites (albendazole sulphoxide and albendazole sulphone) were analysed using a modified high-pressure liquid chromatography method. For both metabolites, there was no significant difference in the biological half-life ( t(1/2)), time to reach peak concentration (t(max)) and mean residence time (MRT) between men and women, whereas apparent oral clearance (Cl(p)/F) and apparent distribution volume (V(d)/F) were less and serum peak concentration (C(max)), area under the serum concentration-time curve (AUC) and area under the first moment curve (AUMC) were more in women than in men. These observations indicate sex dimorphism in pharmacokinetics of albendazole (observed for albendazole sulphoxide and albendazole sulphone) which were explained on the basis of a change in fraction of the main drug turned to metabolite as a result of more extensive first-pass metabolism of the main drug in the liver of adult female subjects.     

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 (kapo and kab, 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 MRTiv and MRTpo were derived. Mean absorption time (MAT = MRTpo - MRTiv) is also time-dependent, contrary to findings previously published for a model of EHC with a continuous time lag. MAT is also dependent on kapo, kba and the hepatic extraction ratio. The difference between MRTpos for two formulations with unequal kapo 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 pharmacokinetic studies for compounds which are extensively cycled in bile.     

A method for calculating the mean residence times of catenary metabolites

A method for calculating the mean residence times of metabolites in the body, systemic circulation, and peripheral tissue is described. The calculations require the AUC, AUMC, and derivatives of the plasma concentration versus time curves of the metabolite and its precursor. The method is applicable to metabolites with any precursor order and does not require separate administration of the metabolite. The approach is applied to published data for the primary and secondary metabolites of ketamine.