A general method for calculating the mean transit times and distribution rate parameters of catenary metabolites.

A general method for calculating the mean transit times and distribution rate parameters is described. The calculations require the AUC, AUMC, and derivatives of the plasma concentration profiles of the metabolites and its precursor. The method is applicable to catenary 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 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.     

Volumes of distribution and mean residence time of drugs with linear tissue distribution and binding and nonlinear protein binding

Based on a generalized model, equations for calculating the mean residence time in the body at single dose (MRT) and at steady state (MRT _ss), apparent steady-state volume of distribution ( ) and steady-state volume of distribution (V _ss) are derived for a drug exhibiting nonlinear protein binding. Interrelationships between andV _ss as well as betweenMRT andMRT _ss are also discussed and illustrated with simulated data. In addition, a method for estimating the central volume of distribution of the bound drug and the sum of the central volume of distribution of the unbound drug and the area under the first moment curve of distribution function for drugs with nonlinear protein binding is proposed and illustrated with both simulated and published data.     

Drug and metabolite concentrations combined in predicting steady-state concentrations from test doses

The first day test dose versus steady-state relationship for predicting drug doses was evaluated for the situation where metabolites are produced. An organ clearance model incorporated into a digital computer program simulated drug and metabolite disposition. When the terminal elimination rate for metabolite was similar to that of its precursor, the drug and metabolite concentrations could be summed for use in test dose predictions as the resulting accumulation ratios were similar. However, if an active metabolite is eliminated more slowly than its precursor, future studies should consider these concentrations separately for predictive purposes. The theoretical results agreed with concentration data obtained from a study of patients who took imipramine.     

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.     

Properties of the Michaelis-Menten equation and its integrated form which are useful in pharmacokinetics

Some old equations are reviewed and some new equations have been derived which indicate certain properties of the Michaelis-Menten equation and its integrated forms. Simulated data which obey Michaelis-Menten kinetics have been plotted in various ways to illustrate special relationships. An equation is derived which accurately estimates the slope of the apparently linear decline (k_o)of concentrations from the values of C_o, K_m,and V_m.This indicates the hybrid nature of k_o.It is pointed out that if a metabolite is formed by Michaelis-Menten kinetics, then (a)one would not expect linear plots of cumulative amount of metabolite excreted in the urine vs. time, and (b)the plasma clearance of the drug will change with dose, and the plasma clearance of the drug would be expected to be different following administration of the same dose in a rapidly available and a slowly available dosage form. The distortion in parameter values when data arising from Michaelis-Menten kinetics are evaluated by classical linear pharmacokinetics is indicated.     

Absorption,distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects

1.?Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor.

2.?The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50?μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600?mg oral dose of alectinib in the first period, and a single 600?mg/67?μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects.

3.?The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5?L/h, volume of distribution was 475?L and the hepatic extraction ratio was low (0.14).

4.?Near-complete recovery of administered radioactivity was achieved within 168?h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively.

5.?This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans.     

Testicular distribution and toxicity of a novel LTA4H inhibitor in rats

JNJ 40929837, a novel leukotriene A4 hydrolase inhibitor in drug development, was reported to induce testicular toxicity in rats. The mechanism of toxicity was considered to be rodent specific and not relevant to humans. To further investigate this finding in rats, the distribution and toxicokinetics of JNJ 40929837 and its two metabolites, M1 and M2, were investigated. A quantitative whole body autoradiography study showed preferential distribution and retention of JNJ 40929837-derived radioactivity in the testes consistent with the observed site of toxicity. Subsequent studies with unlabeled JNJ 40929837 showed different metabolite profiles between the plasma and testes. Following a single oral 50 mg/kg dose of JNJ 40929837, M2 was the primary metabolite in plasma whereas M1 was the primary metabolite in testes. The exposure of M1 was 386-fold higher in the testes compared to plasma whereas M2 had limited exposure in testes. Furthermore, the T_max of M1 was 48 h in testes suggesting a large accumulation potential of this metabolite in testes compared to plasma. Following six months of repeated daily oral dosing, M1 accumulated approximately five-fold in the testes whereas the parent did not accumulate. These results indicate that the toxicokinetic profiles of JNJ 40929837 and its two metabolites in testes are markedly different compared to plasma and support the importance of understanding the toxicokinetic profiles of compounds and their metabolites in organs/tissues where toxicity is observed.     

Steady-state volume of distribution of two-compartment models with simultaneous linear and saturated elimination

The model-independent estimation of physiological steady-state volume of distribution (\(V_{dss,p}\)), often referred to non-compartmental analysis (NCA), is historically based on the linear compartment model structure with central elimination. However the NCA-based steady-state volume of distribution (\(V_{dss,nca}\)) cannot be generalized to more complex models. In the current paper, two-compartment models with simultaneous first-order and Michaelis–Menten elimination are considered. In particular, two indistinguishable models \(\mathrm{M}_1\) and \(\mathrm{M}_2\), both having central Michaelis–Menten elimination, while first-order elimination exclusively either from central or peripheral compartment, are studied. The model-based expressions of the steady-state volumes of distribution \(V_{dss,\mathrm{M}_i}\,\,(i=1,2)\) and their relationships to NCA-based \(V_{dss,nca}\) are derived. The impact of non-linearity and peripheral elimination is explicitly delineated in the formulas. Being concerned with model identifiability and indistinguishability issues, an interval estimate of \(V_{dss,p}\) is suggested.     

Theorems and implications of a model independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. I. Derivations and theoretical analysis

The approach presented enables a model independent representation of the pharmacokinetics of drugs with a linear disposition and some drugs with a nonlinear disposition. The approach is based on a decomposition of the drug disposition into an elimination function q(c) and a distribution function h(t). The qfunction represents the net effect of all disposition processes which work toward a reduction in the systemic drug level. The hfunction represents the net effect of all disposition processes which slow down the rate of decline of the systemic drug level by returning drug from the peripheral environment to the systemic circulation. Several theorems relating qand hto the drug disposition are presented which uniquely define these functions mathematically. The disposition decomposition is of particular significance in three main areas of pharmacokinetics: (1) evaluation of drug absorption, (2) drug level predictions including steady state predictions, and (3)elucidation of drug disposition kinetics. The practical significance of the decomposition method in these three areas is discussed, and various procedures for the application of the method are proposed. The decomposition method represents a model independent alternative to pharmacokinetic models such as linear compartmental models, the recirculation model, and some physiologic models. This also includes nonlinear forms of such models, as long as the nonlinearity is due to a central nonlinear elimination. The greatest promise and significance of the disposition decomposition approach appears to be its application to nonlinear pharmacokinetics. In contrast to linear pharmacokinetics the kinetic analysis in such cases has been limited to model dependent methods employing specific pharmacokinetic models, due to the lack of model independent alternatives. The novel development presented offers such alternatives. For some applications these alternatives appear more rational in the sense that the analysis becomes more general and objective and may be based on fewer assumptions.     

Pharmacokinetics,distribution, and disposition of esaxerenone,a novel,highly potent and selective non-steroidal mineralocorticoid receptor antagonist,in rats and monkeys

1.?Esaxerenone (CS-3150) is a novel non-steroidal mineralocorticoid receptor antagonist. The pharmacokinetics, tissue distribution, excretion, and metabolism of esaxerenone were evaluated in rats and monkeys.

2.?Following intravenous dosing of esaxerenone at 0.1–3?mg/kg, the total body clearance and the volume of distribution were 3.53–6.69?mL/min/kg and 1.47–2.49?L/kg, respectively, in rats, and 2.79–3.69?mL/min/kg and 1.34–1.54?L/kg, respectively, in monkeys. The absolute oral bioavailability was 61.0–127% in rats and 63.7–73.8% in monkeys.

3.?After oral administration of [¹⁴C]esaxerenone, the radioactivity was distributed widely to tissues, with the exception of a low distribution to the central nervous system. Both in rats and in monkeys, following oral administration of [¹⁴C]esaxerenone the main excretion route of the radioactivity was feces.

4.?Five initial metabolic pathways in rats and monkeys were proposed to be N-dealkylation, carboxylation, hydroxymethylation, O-glucuronidation, and O-sulfation. The oxidized metabolism was predominant in rats, while both oxidation and glucuronidation were predominant in monkeys.     

Pharmacokinetic and Metabolic Disposition of p-Chloro-m-xylenol (PCMX) in Dogs

The pharmacokinetic and metabolic profile of p-chloro-m-xylenol (PCMX) was studied in healthy mongrel dogs after intravenous and oral administration of single doses of 200 and 2000 mg of PCMX, respectively. Calculation of pharmacokinetic parameters was based on compartmental and noncompartmental methods. The mean pharmacokinetic parameters of elimination half-life and mean residence time were 1.84 and 1.69 hr, respectively. The apparent volume of distribution at steady state was estimated to be 22.4 liters, and the plasma clearance was 14.6 liters/hr. The bioavailability of PCMX was 21%, indicating low absorption for this drug. PCMX's metabolite data show that a presystemic elimination process (first-pass effect) is also occurring. PCMX plasma concentrations after intravenous administration of 500-, 200-, and 100-mg doses were found to be proportional to the dose given, demonstrating that the pharmacokinetic profile of PCMX is linear over the dose range studied. Biotransformation studies showed that urinary excretion was not the major route for rapid elimination of unchanged PCMX and almost all material excreted in urine was associated with the conjugated species (glucuronides and sulfates). Statistical significant differences were not found (P > 0.05) between the percentages excreted in urine of PCMX and its conjugated metabolites after intravenous and oral administration. The percentages excreted in urine after iv and oral doses of unchanged PCMX were, respectively, 0.45 and 0.37; total conjugates, 46.3 and 43.3; sulfates, 38.1 and 33.2; and glucuronides, 8.2 and 10.2.     

Tissue distribution and urinary excretion of inorganic arsenic and its methylated metabolites in mice following acute oral administration of arsenate.

The relationship of exposure dose and tissue concentration of parent chemical and metabolites is a critical issue in cases where toxicity may be mediated by a metabolite or by parent chemical and metabolite acting together. This has emerged as an issue for inorganic arsenic (iAs), because both its trivalent and pentavalent methylated metabolites have unique toxicities; the methylated trivalent metabolites also exhibit greater potency than trivalent inorganic arsenic (arsenite, As(III)) for some endpoints. In this study, the time-course tissue distributions for iAs and its methylated metabolites were determined in blood, liver, lung, and kidney of female B6C3F1 mice given a single oral dose of 0, 10, or 100 micromol As/kg (sodium arsenate, As(V)). Compared to other organs, blood concentrations of iAs, mono- (MMA), and dimethylated arsenic (DMA) were uniformly lower across both dose levels and time points. Liver and kidney concentrations of iAs were similar at both dose levels and peaked at 1 h post dosing. Inorganic As was the predominant arsenical in liver and kidney up to 1 and 2 h post dosing, with 10 and 100 micromol As/kg, respectively. At later times, DMA was the predominant metabolite in liver and kidney. By 1 h post dosing, concentrations of MMA in kidney were 3- to 4-fold higher compared to other tissues. Peak concentrations of DMA in kidney were achieved at 2 h post dosing for both dose levels. Notably, DMA was the predominant metabolite in lung at all time points following dosing with 10 micromol As/kg. DMA concentration in lung equaled or exceeded that of other tissues from 4 h post dosing onward for both dose levels. These data demonstrate distinct organ-specific differences in the distribution and methylation of iAs and its methylated metabolites after exposure to As(V) that should be considered when investigating mechanisms of arsenic-induced toxicity and carcinogenicity.     

Mean Residence Times and Distribution Volumes for Drugs Undergoing Linear Reversible Metabolism and Tissue Distribution and Linear or Nonlinear Elimination from the Central Compartments

Equations for the mean residence times in the body (MRT) and in the central compartment (MRTc) are derived for bolus central dosing of a drug and its metabolite which undergo linear tissue distribution and linear reversible metabolism but are eliminated either linearly or nonlinearly (Michaelis–Menten kinetics) from the central compartments. In addition, a new approach to calculate the steady-state volumes of distribution for nonlinear systems (reversible or nonreversible) is proposed based on disposition decomposition analysis. The application of these equations to a dual reversible two-compartment model is illustrated by computer simulations.     

Surgically affected sulfisoxazole pharmacokinetics in the morbidly obese

Intestinal bypass surgery in 4 morbidly obese females (110-150 kg) had no permanent effect on the rate or amount of sulfisoxazole absorption. The loss of weight up to 44 per cent within an individual over a year's time had no significant effect on the apparent volumes of distribution or other pharmacokinetic parameters of sulfisoxazole and its N⁴- acetylsulfisoxazole metabolite. Dosing of this drug on a mgkg^{? 1} basis is contraindicated. Renal clearances of sulfisoxazole were reasonably constant within a study but those of the N⁴-acetylsulfisoxazole decreased with time. Integrated pharmacokinetic models were applied to plasma and urine data to estimate the metabolic clearance of sulfisoxazole and the apparent volume of distribution of the N⁴-acetylsulfisoxazole. Sulfisoxazole solution is absorbed readily by primarily a zero order process after a short lag period, indicative of rate-determining gastric emptying. The classical Bratton-Marshall assays were compared with an HPLC assay of both drug and metabolite. There was greater confidence in plasma levels of the metabolite from the HPLC method.     

A general model of metabolite kinetics following intravenous and oral administration of the parent drug

A model of metabolite pharmacokinetics is developed in terms of residence time distributions and derived non-compartmental measures. It provides quantitative insight into factors determining the concentration-time curve of metabolite following intravenous and oral administration of the precursor drug. The AUCs and higher curve moments (mean residence times and relative dispersions) are calculated/predicted and their dependence on mean absorption time, fraction of first-pass metabolism and intrinsic disposition residence times of the parent drug and metabolite, respectively, is discussed. An AUC-based method for the determination of the first-pass effect is proposed which is not influenced by drug absorption. The approach is valid for linear pharmacokinetic systems exhibiting hepatic and renal elimination of the precursor drug; it is not restricted to specific compartmental models. Limitations of previous concepts of metabolite kinetics are defined. Criteria are presented for the appearance of concave metabolite curves in a semi-logarithmic scale.     

Pharmacokinetics

Pharmacokinetics (PK) is the study of the time course of the absorption, distribution, metabolism and excretion (ADME) of a drug, compound or new chemical entity (NCE) after its administration to the body. Following a brief introduction as to why knowledge of the PK properties of an NCE is critical to its selection as a lead candidate in a drug discovery program and/or its use as a functional research tool, the present article presents an overview of PK principles, including practical guidelines for conducting PK studies as well as the equations required for characterizing and understanding the PK of an NCE and its metabolite(s). A review of the determination of in vivo PK parameters by non-compartmental and compartmental methods is followed by a brief overview of allometric scaling. Compound absorption and permeability are discussed in the context of intestinal absorption and brain penetration. The volume of distribution and plasma protein and tissue binding are covered as is the clearance (systemic, hepatic, renal, biliary) of both small and large molecules. A section on metabolite kinetics describes how to estimate the PK parameters of a metabolite following administration of an NCE. Lastly, mathematical models used to describe pharmacodynamics (PD), the relationship between the NCE/compound concentration at the site of action and the resulting effect, are reviewed and linked to PK models in a section on PK/PD.     

Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination

The problem of finding the steady-state volume of distribution V(ss) for a linear pharmacokinetic system with peripheral drug elimination is considered. A commonly used equation V(ss) = (D/AUC)*MRT is applicable only for the systems with central (plasma) drug elimination. The following equation, V(ss) = (D/AUC)*MRT(int), was obtained, where AUC is the commonly calculated area under the time curve of the total drug concentration in plasma after intravenous (iv) administration of bolus drug dose, D, and MRT(int) is the intrinsic mean residence time, which is the average time the drug spends in the body (system) after entering the systemic circulation (plasma). The value of MRT(int) cannot be found from a drug plasma concentration profile after an iv bolus drug input if a peripheral drug exit occurs. The obtained equation does not contain the assumption of an immediate equilibrium of protein and tissue binding in plasma and organs, and thus incorporates the rates of all possible reactions. If drug exits the system only through central compartment (plasma) and there is an instant equilibrium between bound and unbound drug fractions in plasma, then MRT(int) becomes equal to MRT = AUMC/AUC, which is calculated using the time course of the total drug concentration in plasma after an iv bolus injection. Thus, the obtained equation coincides with the traditional one, V(ss) = (D/AUC)*MRT, if the assumptions for validity of this equation are met. Experimental methods for determining the steady-state volume of distribution and MRT(int), as well as the problem of determining whether peripheral drug elimination occurs, are considered. The equation for calculation of the tissue-plasma partition coefficient with the account of peripheral elimination is obtained. The difference between traditionally calculated V(ss) = (D/AUC)*MRT and the true value given by (D/AUC)*MRT(int) is discussed.     

Theorems and implications of a model-independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. IV. Exact relationship between the terminal log-linear slope parameter beta and drug clearance

An exact formula relating the terminal log-linear beta parameter and the drug clearance is derived. The expression is valid for drugs with a linear, polyexponential disposition kinetics. The formula is useful for calculating the clearance when the clearance has changed between drug administrations and requires only drug level data from the terminal, log-linear elimination phase in addition to data from a single separate i.v. administration in the same subject. Data from an i. v. administration are necessary in order to apply the disposition decomposition technique to isolate and uniquely define the distribution kinetics in terms of the distribution function h(t).The different clearances can then be calculated from the beta values of the log-linear terminal drug level data and the parameters of h(t).The theoretical basis of the method and its assumptions and limitations are discussed and various pertinent theorems are presented. A computer program enabling an easy implementation of the proposed method is also presented. The mathematical and computational procedures of the method are demonstrated using kinetic data from i.v. and oral administrations of cimetidine, diazepam, and pentobarbital in human subjects. The classical V. beta method of approximating the clearance as the product of volume of distribution and beta is considered for comparison. For the three drugs considered the V. beta method which assumes a single exponential disposition kinetics leads to excessive errors when applied in absolute clearance comparisons. However, when applied in relative comparisons in the form of the beta correction the errors cancel out to some extent depending on the magnitude of the distribution kinetic effect. Whenever possible it is advisable to apply the proposed method to avoid such errors.     

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.