Mean Residence Time of Oral Drugs Undergoing First-Pass and Linear Reversible Metabolism

Equations for the mean residence times in the body (MRT) and AUMC/AUC of a drug and its metabolite have been derived for an oral drug undergoing first-pass and linear reversible metabolism. The mean residence times of the drug or interconversion metabolite in the body after oral drug are described by equations which include the mean absorption time (MAT), the mean residence times of the drug or metabolite in the body after intravenous administration of the drug, the fractions of the dose entering the systemic circulation as the parent drug and metabolite, and the systemically available fractions of the drug (F _p ^p) or metabolite (F _m ^p). Similarly, the AUMC/AUC of the drug and metabolite after oral drug can be related to the MAT, ratios of the fraction of the dose entering the systemic circulation to the systemically available fraction, the first-time fractional conversion of each compound, and AUMC/AUC ratios after separate intravenous administration of each compound. The F _p ^p and F _m ^p values, in turn, are related to the first-pass availabilities of both drug and metabolite and the first-time fractional conversion fractions. The application of these equations to a dual reversible two-compartment model is illustrated by computer simulations.     

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.     

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.     

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.     

Mean time and first-pass metabolism

Summary The theoretical principles are outlined for estimating the fraction of a drug undergoing first-pass metabolism using only the plasma levels found after a single oral dose. Data for 3 drugs are used to illustrate the method. It involves analysis of the parent drug and the metabolite formed during the first passage through the gut wall and liver and evaluation of their total mean times. The mean time characteristics of molsidomine, nortriptyline and propranolol are considered and they confirm the theoretically deduced dependency of the mean time of the parent drug and the metabolite. Whether the results are more precise than those obtained from comparison of areas after oral and intravenous administration is discussed. From the data presented it is clear that the mean time method depends on the scatter inherent in the data. In order to estimate the true first-pass effect, greater scatter requires an increased number of data pairs, i.e. subjects. If intravenous data are not available, however, the method described provides a rough but worthwhile estimate of the first pass effect.Dedicated to Professor Dr. H.J. Dengler, Bonn, on the ocassion of his 60th birthday     

The Role of Metabolites in Bioequivalency Assessment. II. Drugs with Linear Pharmacokinetics and First-Pass Effect

Simulations were conducted to address the question of whether metabolite data are required for bioequivalence evaluation of immediate release formulations with drugs exhibiting linear pharmacokinetics and first-pass effect. Plasma level-time profiles were generated for parent drug and metabolite using relevant rate constants obtained from a bivariate normal distribution and designated random error. Simulation results showed that the need for metabolite data (C_max) in the assessment of bioequivalence depends on the relative variability between the absorption process of the drug and first-pass route for metabolite(s). The importance of metabolite C_max data in the evaluation of rate of availability is clearly demonstrated for drugs with a high degree of intra-subject variation in the first-pass metabolism compared to the absorption process of the drug. Under such conditions, a wider confidence interval was found for the metabolite rather than parent drug. Opposite results were obtained when the intra-subject variance was high for drug absorption relative to first-pass effect. Discrepancies were observed for the scenarios in which the elimination pathway of the metabolite is more variable than the absorption process of the drug. The simulation results were in agreement with real bioequivalence data. It is thus recommended that, in the absence of the information on the relative variability of absorption and first-pass process, both parent drug and metabolite data be included for documentation of bioequivalence, should the metabolite(s) play an important role in the determination of efficacy and safety of the drug.     

Theoretical relationships between area under the curve and route of administration of drugs and their precursors for evaluating sites and pathways of metabolism

The bioavailability of a drug administered extrasystemically is a measure of the initial extraction of a compound by a series of eliminating events involving the intestinal mucosal enzymes, the gut bacterial microflora, the liver, and the lung. A theoretical analysis is presented to differentiate the process of gut wall elimination and hepatic removal of a drug during this first-pass effect. The area under the blood concentration--time curve (AUC) for a drug and its metabolite is shown to be useful in determining the presence of these processes when a drug and its metabolite are administered concomitantly by different routes of administration. Furthermore, the fraction of a precursor transformed to its metabolite also can be determined by pharmacokinetic analysis of the AUC of a drug and its metabolite after administration of both substances.     

The area under the curve of metabolites for drugs and metabolites cleared by the liver and extrahepatic organs. Its dependence on the administration route of precursor drug

The venous equilibrium model (or well-stirred model) is used to determine the area under the blood concentration vs. time curve of a metabolite formed from a precursor drug. It will be shown that the AUC of a metabolite will change according to the route of precursor drug administration(whether intraarterially, intravenously, via the portal vein, or orally) when the drug and/or metabolite is eliminated by more than one organ. Elimination includes hepatic and extrahepatic metabolism and renal excretion. The validity of the model is probed by using literature data for drug and metabolite areas. Finally, the use of metabolite areas for evaluating the complete/incomplete absorption or orally administered precursor drug is discussed.     

A pharmacokinetic approach to the establishment of biopharmaceutic characteristics of different acetylsalicylic acid formulations in man

Eleven acetylsalicylic acid (ASA) formulations were administered to 26 healthy volunteers in a cross-over design. The properties of the preparations differed from conventional, effervescent, buffered to buccal. The objectives of this study were:

• 1 Consideration of the general aspects of a biopharmaceutical study: which parameter for which biopharmaceutic characteristic?
• 2 Measurement of the kinetic parameters of ASA: first-pass effect, mean residence time, mean appearance time, total body clearance, apparent volume of distribution, half-lives, etc.
• 3 Comparison of the formulations.

Most of the formulations yield mean residence times for ASA of 0.3–1.0h, which do not differ significantly (p > 0.05). For most of the products the first-pass effect is about 40 per cent; the average values of the apparent volume of distribution and whole body clearance, corrected for the first-pass effect, are about 201 and 650 ml min^?1, respectively. Peak levels are reached slowly for the buccal formulations, and rapidly for the buffered products. It is difficult, especially for ASA, to characterize the gastro-intestinal absorption with pharmacokinetic model parameters, because the first-pass effect is large and often elimination of ASA is faster than absorption. The model-independent approach has the special advantages of calculating reliable pharmacokinetic parameters, and creating theoretical possibilities to characterize the absorption patterns of the different formulations in a quantitative way. No significant differences in the values of the parameters are found between most of the formulations. The ASA first-pass effect is reasonably constant and buccal application has no advantage. Enteric coating of the outer layer of ASA formulations causes inconsistent absorption and may be categorized under ‘artificial mistakes’.     

Determination of metabolite pharmacokinetics for orally administered prodrugs

The theoretical evaluation of a pharmacokinetic precursor/metabolite model was accomplished utilizing an integral approach based on clearance. Particular attention was paid to prodrugs where a single active intermediate results directly from the parent drug. This model, however, can be utilized for any drug in which a single first-pass metabolic adduct results. Complete elucidation of the first-pass and metabolic systemic pharmacokinetics is possible when plasma and urine concentration data are available after only oral drug administration. The generality of the model does not require prior knowledge of whether the metabolite was formed systemically or presystemically, and only limited metabolic pathway profiling. The model was applied to the evaluation of the angiotensin-converting enzyme inhibitor prodrug pentopril.     

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, Fabs, 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 systematically, the general solution for AUC(m) is the product of Fabs 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 Fabs. When this fraction is divided into the overall systemic availability or Fsys, the drug availability from the first-pass organs, F, may be found.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Cyclosporin-erythromycin interaction in normal subjects.

We studied the pharmacokinetic interaction between cyclosporin (CYA) and erythromycin in normal subjects. Plasma CYA concentrations were measured by high performance liquid chromatography (h.p.l.c.) and radioimmunoassay (RIA) and estimates of metabolite formation were obtained from inter-assay differences between these measurements. Erythromycin significantly increased the maximum concentration and the area under concentration-time curve. Time to maximum concentration and apparent oral clearance of CYA were significantly decreased. The half-life, however, was not altered. Significant reductions in the proportion of apparent metabolite were observed at times of maximum CYA concentrations but not at later time periods (12 and 24 h). The mechanism of the drug interaction appears to be decreased hepatic first-pass metabolism but an effect on CYA absorption cannot be excluded. These results on normal subjects confirm that patients administered CYA and erythromycin risk CYA toxicity. However, the risk can be reduced by dose reduction based on more frequent CYA monitoring or by using a different antibiotic.     

Drug metabolite concentration-time profiles: influence of route of drug administration.

In order to assess the contribution of an active metabolite to the overall pharmacological response following drug administration it is necessary to characterise the metabolite concentration-time profile. The influence of route of drug administration on metabolite kinetics has been investigated by computer simulation. Comparisons between simulated profiles and published concentration-time data have been carried out. A route dependence in metabolite concentration-time curves is readily apparent provided the metabolite kinetics are formation rate limited and the hepatic clearance of drug is greater than 25 l/h (medium to highly cleared). Oral drug administration produces a triphasic metabolite concentration-time profile whereas only two phases are discernable after intravenous drug administration. The magnitude of the difference in maximum metabolite concentration is directly proportional to the hepatic clearance of drug due to first-pass metabolite production. The route dependence in the shape of the metabolite concentration-time curves is most dramatic when the absorption and distribution of drug and the elimination of metabolite is rapid. A reduction in the rate of either of these processes alters the shape of the metabolite concentration-time profile such that the consequence of first-pass metabolite formation may be reduced.     

Site-specific drug delivery systems. III. Nasal drug delivery

The nasal cavity has a large surface and a rich blood supplied mucosa. Drugs absorbed by blood vessels pass directly into the systemic circulation, thereby avoiding first-pass metabolism. Numbers of factors limit the intranasal absorption of drugs, especially peptide and protein drugs. These factors are the epithelial and mucus barrier, the rapid mucociliar clearance and the enzymatic activity. Increasing the residence time of the drug formulation in the nasal cavity and a period of contact with nasal mucosa, may improve drug absorption. Approaches to increase the residence time of drug formulations in the nasal cavity usually involve the use of microspheres, liposomes and bioadhesive gels.     

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.     

Generalizations in linear pharmacokinetics using properties of certain classes of residence time distributions. II. Log-concave concentration-time curves following oral administration

The present approach enables a noncompartmental assessment of log-concave plasma concentration-time profiles following oral drug administration. Observed log-concavity corresponds to a nonparametric class of residence time distributions with the following properties: (1) The fractional rate of elimination kB(t) (failure rate of the distribution) increases monotonically until reaching the terminal exponential coefficient kB,Z. (2) The relative dispersion of body residence times CVB2 (ratio of variance to the squared mean, VBRT/MBRT2) acts as a shape parameter of the curve. The role of the input process in determining the shape of the concentration profile is discussed. In this connection evidence is provided for the importance of log-concave percent undissolved versus time plots, introducing the general concept of a time-varying fractional rate of dissolution. The governing factor for the appearance of log-concavity is the ratio of mean absorption time to mean disposition residence time (MAT/MDRT); this factor exceeds a particular threshold value which depends on the distributional properties of the drug. Generalizing previous approaches which are valid for first-order input processes, the "flip-flop" phenomenon and the problem of "vanishing of exponential terms" are explained using fewer assumptions. Upper bounds for the elimination time (more than 90% eliminated) and the cutoff error in AUC determination are presented. The concept of log-concavity reveals general features of the pharmacokinetic behavior of oral dosage forms exhibiting a dominating influence of the absorption/dissolution process.     

Mean residence time of drugs administered non-instantaneously and undergoing linear tissue distribution and reversible metabolism and linear or non-linear elimination from the central compartment

Based on disposition decomposition analysis (DDA), equations for the mean residence times (MRT) in the body are derived for a drug and its interconversion metabolite that undergo linear tissue distribution and linear or non-linear elimination from the central compartment after non-instantaneous administration of the drug. The MRT of the drug after non-instantaneous input can be related to the MRT of the drug after intravenous administration, the ratio of the total area under the plasma concentration—time curve of the drug after non-instantaneous administration to that after intravenous administration, the bioavailability of the drug, and the mean input time of the drug. Similar relationships also exist for the MRT of the interconversion metabolite after non-instantaneous input of the drug. The application of these equations to a non-linear reversible metabolic system is illustrated with computer simulations.     

Mean residence time

The definition of mean residence time in the strict sense of mathematical statistics is deduced. It is demonstrated that the area-normalized concentration time curve is an estimate of the probability density function for residence times of drug molecules in the pharmacokinetic system, provided that the area under the concentration-time profile is proportional to the total amount eliminated from the system. Criticisms (8) on the determination of the mean residence time are refuted. The linearity of pharmacokinetic systems is defined, based on the statistical interpretation of these systems.     

Pharmacokinetics of epirubicin emulsion and solution in rabbits after intrahepato-arterial and intravenous injection.

The study reports pharmacokinetic findings on the disposition of a formulated emulsion of epirubicin in rabbits as compared to plain epirubicin solution after intrahepato-arterial and intravenous administration. The dose of epirubicin used was 1 mg/kg body weight. Blood samples were collected at several time points up to 6 h after administration. Serum concentrations of epirubicin were measured by liquid chromatography with fluorometric detection. The area under serum concentration-time curve (AUC infinity 0) is smallest after intrahepato injection of epirubicin emulsion. This, together with the highest apparent volume of distribution (Vss) suggest a possible targetting effect. Although the mean residence times are similar, intrahepato injection of emulsion apparently has the largest clearance. Difference in bioavailability in the general circulation between the 2 routes of administration also suggests a certain degree of liver first-pass metabolism of the drug. In view of these findings, further investigation and assessment are worthwhile for future application in human subjects.