Application of Organ Clearance to Estimation of the In Vivo Hepatic Extraction Ratio

Mehvar, Reza

doi:10.2174/1574884710666150817104746

Cited by 14 publications

(8 citation statements)

References 12 publications

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“…Given that the blood-to-plasma ratio is~0.9, [25] CL values based on plasma or serum can be assumed to be very similar to those based on blood. [26] In this study, the serum CL/F was found to have a mean of 0.297 l/h per kg, which is lower than previously reported in young healthy volunteers. [27][28][29][30] Lidocaine is commonly described as a rapidly cleared drug with a high level of hepatic extraction (>0.7), wherein its clearance would be primarily blood-flow-dependent.…”

Section: Discussioncontrasting

confidence: 69%

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Rectus sheath single-injection blocks: a study to quantify local anaesthetic absorption using serial ultrasound measurements and lidocaine serum concentrations

Primrose

Nebaihi

Brocks

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Rectus sheath blocks are an established option for analgesia following abdominal surgery, but pharmacokinetic data are limited. This study sought to characterise the absorption of lidocaine injectate and the pharmacokinetics of lidocaine after rectus sheath injection. Methods Bilateral rectus sheath single‐injection blocks were given to 10 patients undergoing general or urological surgery. Afterwards, serial lidocaine serum levels and ultrasound measurements of the rectus sheath injectate reservoir were collected. Key findings Injectate within the rectus sheath was visible with ultrasound up to 12 h after injection. However, the rate of drug absorption exceeded that of injectate disappearance. Peak serum concentration occurred within 30 min with average peak concentrations of 1.65 μg/ml. Lidocaine clearance was lower than reported in young healthy subjects. The body mass index positively correlated with lidocaine terminal phase half‐life, and clearance negatively correlated with age. Conclusions The study provides the first data describing lidocaine pharmacokinetics after rectus sheath injection. Peak serum concentrations transiently achieved systemic levels associated with pain relief after a single bolus injection. The data from this study could be used to develop a regime using single shot rectus sheath blockade with a bolus of lidocaine followed by infusion using bilateral rectus sheath catheters.

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Section: Discussioncontrasting

confidence: 69%

“…Given that the blood‐to‐plasma ratio is ~0.9, CL values based on plasma or serum can be assumed to be very similar to those based on blood . In this study, the serum CL/F was found to have a mean of 0.297 l/h per kg, which is lower than previously reported in young healthy volunteers .…”

Section: Discussioncontrasting

confidence: 45%

Rectus sheath single-injection blocks: a study to quantify local anaesthetic absorption using serial ultrasound measurements and lidocaine serum concentrations

Primrose

Nebaihi

Brocks

et al. 2019

Journal of Pharmacy and Pharmacology

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“…After intravenous administration of the drug, the systemic Cl is estimated from the blood concentration-time data, and an estimate of Clh is obtained by either assuming Clh is equal to systemic clearance (i.e., for drugs with hepatic elimination only) or by subtracting renal Cl from the systemic clearance (i.e., for drugs with both renal and hepatic elimination), as discussed in detail recently (23). An estimate of Eh is then obtained using the calculated Clh and an average Qh.…”

Section: Oral Clearance and Intrinsic Clearancementioning

confidence: 99%

“…The estimates of Eh value can then be used to predict the pharmacokinetics and blood concentration-time profiles of the drug in the presence of changes in the physiologic determinants of clearance such as organ blood flow, intrinsic clearance, or fub. The assumptions inherent to this type of calculation and the ramifications of using plasma or serum concentrations, instead of blood concentrations, and/or liver plasma flow, instead of liver blood flow, were recently discussed in detail (23). Briefly, it was shown that if plasma clearance and hepatic blood flow are used, the estimated Eh would be accurate only if the blood: plasma concentration (B:P) ratio of the drug is equal to 1.…”

Section: Oral Clearance and Intrinsic Clearancementioning

confidence: 99%

“…Briefly, it was shown that if plasma clearance and hepatic blood flow are used, the estimated Eh would be accurate only if the blood: plasma concentration (B:P) ratio of the drug is equal to 1. However, the use of the plasma concentrations and plasma liver flow will always result in an overestimation of the true Eh unless the drug does not penetrate the red blood cells (23).…”

Section: Oral Clearance and Intrinsic Clearancementioning

confidence: 99%

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Clearance Concepts: Fundamentals and Application to Pharmacokinetic Behavior of Drugs

Mehvar

2018

J Pharm Pharm Sci

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Clearance concepts were introduced into the pharmacokinetics discipline in the 1970s and since then have played a major role in characterization of the pharmacokinetic behavior of drugs. These concepts are based on the relationship between organ extraction ratio or clearance and physiologic parameters such as the organ blood flow and the intrinsic capability of the eliminating organ to remove the free (unbound) drug from the body. Several theoretical models have been developed, which define these relationships and may be used to predict the effects of changes in the physiological parameters on various pharmacokinetic parameters of drugs, such as drug clearance. In this communication, the fundamentals of the two most widely used models of hepatic metabolism, namely the well-stirred (venous equilibrium) and parallel-tube (sinusoidal perfusion) models, are reviewed. Additionally, the assumptions inherent to these models and the differences between them in terms of their predictive behavior are discussed. The effects of changes in the physiologic determinants of clearance on the blood concentration-time profiles of drugs with low and high extraction ratio are also presented using numerical examples. Lastly, interesting and unusual examples from the literature are provided where these concepts have been applied beyond their widely known applications. These examples include estimation of the oral bioavailability of drugs in the absence of otherwise needed intravenous data, differentiation between the role of liver and gut in the first-pass loss of drugs, and distinction between the incomplete absorption and first-pass metabolism in the gastrointestinal tract after the oral administration of drugs. It is concluded that the clearance concepts are a powerful tool in explaining the pharmacokinetics of drugs and predicting the changes in their blood concentration-time courses when the underlying physiologic parameters are altered due to age, disease states, or drug interactions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

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Total Clearance and Organ Clearance

Talevi¹,

Bellera²

2021

The ADME Encyclopedia

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Application of Organ Clearance to Estimation of the In Vivo Hepatic Extraction Ratio

Cited by 14 publications

References 12 publications

Rectus sheath single-injection blocks: a study to quantify local anaesthetic absorption using serial ultrasound measurements and lidocaine serum concentrations

Rectus sheath single-injection blocks: a study to quantify local anaesthetic absorption using serial ultrasound measurements and lidocaine serum concentrations

Clearance Concepts: Fundamentals and Application to Pharmacokinetic Behavior of Drugs

Total Clearance and Organ Clearance

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