Effect of Renal Disease on Pharmacokinetics

Atkinson, Arthur J.; Lertora, Juan J.L.

doi:10.1016/b978-0-12-385471-1.00005-2

Cited by 9 publications

(10 citation statements)

References 60 publications

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“…This profile is useful for quantifying absorption and elimination processes of drug as well as formation and elimination processes of metabolite. [13,14] To calculate the maximum amount of B (B max ) and the time to reach the peak (t max ), we take the derivative of Eq. (7), set the derivative, dB/dt, to zero, and rearrange to obtain In Figure 2, we also visualized the Equations (11), (13), and (14) to show that t max decreases and B max increases as the ratio of k 1 to k 2 increases (dashed line).…”

Section: A Basic Model For Prodrug Kineticsmentioning

confidence: 99%

“…[13,14] To calculate the maximum amount of B (B max ) and the time to reach the peak (t max ), we take the derivative of Eq. (7), set the derivative, dB/dt, to zero, and rearrange to obtain In Figure 2, we also visualized the Equations (11), (13), and (14) to show that t max decreases and B max increases as the ratio of k 1 to k 2 increases (dashed line). In other words, when k 2 is smaller than k 1 , the amount of A quickly decreases while the amount of B increases rapidly, reaches a maximum at a shorter time, and then falls off with time.…”

Section: A Basic Model For Prodrug Kineticsmentioning

confidence: 99%

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Understanding the pharmacokinetics of prodrug and metabolite

Cho

Yoon

2018

Transl Clin Pharmacol

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This tutorial explains the pharmacokinetics of a prodrug and its active metabolite (or parent drug) using a two-step, consecutive, first-order irreversible reaction as a basic model for prodrug metabolism. In this model, the prodrug is metabolized and produces the parent drug, which is subsequently eliminated. The mathematical expressions for pharmacokinetic parameters were derived step by step. In addition, we visualized these expressions to help understand the relationship between pharmacokinetic parameters easily. For the elimination rate-limited and formation rate-limited metabolism, we analyzed the plasma drug concentration versus time curve of a prodrug administered intravenously. IntroductionProdrug is a pharmacologically inactive derivative of an active drug and undergoes in vivo biotransformation to release the active drug by chemical or enzymatic cleavages.[1-3] A prodrug strategy is typically used when a pharmacologically active drug has poor solubility or permeability.[1,2] Various chemically or enzymatically labile functional groups have been introduced to improve the properties of the parent drug and decrease the presystemic metabolism.[1,2] Many successful examples have been reviewed in the literature.[1-3] A detailed discussion of prodrugs and their active metabolites (parent drugs) is beyond the scope of this tutorial. Here we focus on the pharmacokinetics of a prodrug and its metabolite to help understand their pharmacokinetic data obtained from preclinical and clinical studies. This will ultimately help define the proper dose of the prodrug needed for efficacy. Theoretical Analysis Prodrug KineticsWhen a prodrug is administered orally, it undergoes complicate processes of absorption, distribution, metabolism, and excretion. To understand these processes for metabolites, Cummings and Martin published results on the excretion and accrual of drug metabolites in 1963. [4] This provides the basis for the pharmacokinetics of drug and its metabolites and can be readily applied to study the pharmacokinetics of prodrug. Since then, many theoretical analyses and reviews, related to prodrug pharmacokinetics, have been published.[5-10] A thorough understanding of prodrug kinetics is daunting and may be achieved using sophisticated physiologically based pharmacokinetic (PBPK) modeling. [11,12] To get some insight pertinent to prodrug kinetics, we consider a simple scheme for the fate of a prodrug (P) after intravenous administration (Fig. 1). A fraction of the prodrug (f) is metabolized and produces a parent drug (D) with a first-order formation rate constant, k f(D) . The drug (D) may be further metabolized to a daughter metabolite (DM 1 ) or excreted. The elimination rate constant of the parent drug, k el(D) , is expressed by the sum of the formation rate constant of the daughter metabolite, k f(DM1) , and the urinary excretion rate constant, k ex(D) . More than one metabolite may be formed with a formation rate constant, k f(PM2) , and then excreted with a rate constant, k ex(PM2) . Otherwise, a fractio...

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Section: A Basic Model For Prodrug Kineticsmentioning

confidence: 99%

Section: A Basic Model For Prodrug Kineticsmentioning

confidence: 99%

Understanding the pharmacokinetics of prodrug and metabolite

Cho

Yoon

2018

Transl Clin Pharmacol

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“…The changes in levofloxacin concentrations in gastric juice indicate that levofloxacin may be actively transported in the stomach, as its concentration in gastric juice was three- to five-fold that in the serum (except during the early stages), which is inconsistent with cis-concentration gradient transport (21), i.e. passive transport of the drug within the body.…”

Section: Discussionmentioning

confidence: 99%

Effect of rabeprazole on the transport and distribution of levofloxacin in rat stomachs

Bao

Qiao

et al. 2014

Experimental and Therapeutic Medicine

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The aim of this study was to determine the transport and distribution characteristics of levofloxacin in the rat stomach and investigate the effects of combination treatment with rabeprazole. A total of 160 Wistar rats were randomly divided into four treatment groups: 50 mg/kg levofloxacin, 100 mg/kg levofloxacin, 50 mg/kg levofloxacin + rabeprazole and 100 mg/kg levofloxacin + rabeprazole. For two hours after intravenous administration, serum, gastric juice and stomach mucosa samples were collected at 15-min intervals, and the levofloxacin concentrations in all the samples were measured to determine the transport and distribution characteristics of levofloxacin in the rat stomach. In the 50 mg/kg levofloxacin and the 100 mg/kg levofloxacin groups, the drug concentration in the gastric juice gradually exceeded the serum concentration within 45–60 min of administration (P<0.05) and the drug concentrations in the gastric body and antrum were higher than those in the serum and the forestomach (P<0.05). At 15–30 min after administration, the drug concentrations in the gastric juice in the 50 mg/kg levofloxacin + rabeprazole and the 100 mg/kg levofloxacin + rabeprazole groups gradually exceeded the serum concentration (P<0.05). However, the levofloxacin concentration in the gastric body and in the antrum did not significantly differ between the two groups (P>0.05). The levofloxacin concentrations in each stomach region in the groups also treated with rabeprazole were higher than those treated with levofloxacin alone, but the differences were not significant. The levofloxacin transport fractions in the stomach in the 50 mg/kg levofloxacin, 100 mg/kg levofloxacin, 50 mg/kg levofloxacin + rabeprazole and 100 mg/kg levofloxacin + rabeprazole groups were 2.36, 2.52, 2.42 and 2.55, respectively, and no significant difference was identified. Levofloxacin may be actively transported in the rat stomach. The levofloxacin concentration in the gastric antrum exceeded that in the forestomach, and the local concentration increased with increasing dosage. Combining a proton pump inhibitor with levofloxacin has little effect on the concentration and distribution of levofloxacin in the stomach within 2 h.

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“…To what extent is a person's ability to notice a drug related to their genotype for enzymes in the cytochrome P450 system, such as CYP2D6 [Atkinson Jr et al, 2012]?…”

Section: Fundamental Questionsmentioning

confidence: 99%

Collecting systematic, introspective reports of pharmacological effects and side-effects

Sarma

2016

Preprint

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The study of subjective, first-person experience is a topic with both philosophical and practical implications. In this article, I discuss the value of collecting a critical mass of prose or verbal descriptions of introspectively determined, subjective effects of pharmacological agents. I suggest that datasets of introspective reports fit in the modern research landscape at the intersection of biomedical informatics and the emerging discipline of contemplative neuroscience. I compare the current proposal to Descriptive Experience Sampling (DES), discuss relevant methodological and conceptual issues in the study of introspection, and provide a list of questions for directing future investigation.

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Effect of Renal Disease on Pharmacokinetics

Cited by 9 publications

References 60 publications

Understanding the pharmacokinetics of prodrug and metabolite

Understanding the pharmacokinetics of prodrug and metabolite

Effect of rabeprazole on the transport and distribution of levofloxacin in rat stomachs

Collecting systematic, introspective reports of pharmacological effects and side-effects

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