Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
LetterLetter to the Editor

Response to Letter to the Editor on “Fractional Clearance for Verapamil N-Demethylation in the Isolated Rat Liver Preparation”

K. Sandy Pang and Qi Joy Yang
Drug Metabolism and Disposition July 2015, 43 (7) 1058-1059; DOI: https://doi.org/10.1124/dmd.115.065227
K. Sandy Pang
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Qi Joy Yang
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

We thank Mehvar (2015) for comments on our recently published article on the estimation of the fractional hepatic clearance of verapamil (VER) that forms norverapamil (NOR) (Yang et al., 2015), and we appreciate this opportunity to respond. In our recent article, we misquoted the values reported by Mehvar et al. 1994 regarding the fraction of infused VER (0.21 and 0.18 for S-VER and R-VER, respectively; eq. 1) and the fraction of extracted VER converted to NOR (0.23 and 0.19 for S-VER and R-VER, respectively; eq. 2) during a single passage through a perfused rat liver preparation at steady state (Mehvar et al., 1994).

In eqs. 1 and 2 below, E is the extraction ratio of VER; Q is the hepatic blood flow rate; Embedded Image is the steady-state outflow concentration of NOR originating from single-pass studies, with Embedded Image as the input VER concentration; Embedded Image are the outflow and inflow concentrations of NOR, respectively, after single-pass perfusion with preformed NOR; and Embedded Image is the hepatic availability of NOR that is assumed to be identical for formed and preformed NOR (Mehvar et al., 1994). Equations 1 and 2 are based on the premise that the formed metabolite suffers immediate sequential removal within the metabolite formation organ; what was detected as the outflow metabolite concentration needs to be corrected for the organ availability of the metabolite, F{mi} (Pang and Gillette, 1979).Embedded Image(1)Embedded Image(2)As noted above, the same term was used by Mehvar et al. (1994) to describe the fraction of infused or extracted VER that is converted to NOR (eq. 1 versus eq. 2). In our experience, the first set of Fm values is not meaningful because these values are influenced by the amount of infused drug as well as by the competing pathways and their saturability. We estimated the second set of Fm values after correction for E or (1 − 0.069) for S-VER and (1 − 0.046) for R-VER in eq. 2 (F values in Table 1 of Mehvar et al. (1994)). The second set of values was 0.23 and 0.19, according to eq. 2. These values are indeed equivalent to hmi, the fraction of hepatic clearance that forms the primary metabolite, mi (eq. 3), according to our study (Yang et al., 2015) and a study by Pang and Kwan (1983) under first-order conditions.Embedded Image(3)We misquoted Mehvar’s Fm value as 0.12 (Yang et al., 2015), when, in fact, their values were 0.23 and 0.19. These E-corrected Fm values would have defined hmi (eq. 3) under first-order conditions. It must be noted, however, that Mehvar used the same term, Fm, for two different occasions; moreover, the term can be confusing because in pharmacokinetic terminology, F indicates availability, whereas f indicates fraction. Mehvar (2015) stated that the estimate of 0.23 did not differ much from 0.31, a value based on the ratio of intrinsic clearance (CLint), and that any difference was due to variability. This may not be the case here, since Mehvar et al. (1994) did not include the appreciable loss of VER and NOR due to adsorption to tubing (loss of 10%–25% of the dose of VER and NOR) and nonlinearity in the data from our study (Yang et al., 2015).

View this table:
  • View inline
  • View popup
TABLE 1

Estimation of fBCLint and CLint for data from Mehvar et al. (1994)

Mehvar (2015) stated that we had misquoted the value of hmi perhaps because we had misunderstood how to interpret single-pass versus recirculating data. Equation 3 is the proper definition of hmi, regardless of the route of drug administration. In our experience, it is not necessary to stipulate oral or intravenous administration for single-pass perfusion, as described in the response by Mehvar (2015). We have performed many perfusion studies and are equipped to interpret the data appropriately. In the single-pass situation, both VER and preformed NOR could be administered into the portal vein and the outflow concentration, Cout, is not returned to the reservoir. The rate of appearance of mi (QCout{mi}) after drug administration in single-pass studies (eq. 2) may be used for the estimation of hmi, when corrected for F{mi}and E, defined by (Cin − Cout)/Cin. By contrast, when an infusion is made into the portal vein in recirculating liver experiments, the condition would mimic oral administration in vivo. When an infusion is made into the reservoir, the condition would mimic intravenous infusion.

Mehvar (2015) stated that use of plasma data to define hmi, with correction for the Embedded Image blood to plasma ratios (Mehvar and Reynolds, 1996), should yield hmi values based on blood data. This is in contrast with our study, in which we stated that blood, and not plasma, concentrations should be used to relate to blood flow and blood clearance in the estimation of hmi (Yang et al., 2015). We recalculated the hmi values (0.23 and 0.19) of Mehvar et al. (1994) and found that, after correction with the B:P ratios (0.758 and 0.66 for S-VER and R-VER and 0.733 and 0.614 for S-NOR and R-NOR, respectively; Robinson and Mehvar, 1996), hmi values did remain similar to those (0.22 and 0.18) based on plasma. However, one could also discuss the effect of fast uptake into red cells but slow release from bound red cells or the possibility of a red cell carriage effect (Pang et al., 1995) on VER metabolism. This could materially affect hmi. We thoroughly investigated this via red cell distribution studies and found that red cell carriage was absent for VER, revealed by estimates of the apparent “on” and “off” rate constants for binding to red cells (Yang et al., 2015). In our recent study, we not only verified the absence of red cell carriage, but we also accounted for the nonlinear red blood cell distribution and protein binding. However, in comparing our plasma protein unbound fraction with the literature, we mistakenly cited the study by Mehvar et al. (1994), instead of the correct study by Mehvar and Reynolds (1996). Mehvar (2015) further commented that in our recent study (Yang et al., 2015), we misquoted the value of (Embedded Image) as 50–130 ml/min, instead of 260 and 430 ml/min (from Mehvar et al., 1994). To gain a clearer view, we recalculated these values, as shown in Table 1.

Our analysis revealed that Mehvar et al. (1994) estimated fPCLint as 260 and 430 ml/min for S-VER and R-VER, respectively. We recalculated fBCLint(cal) and found these values to be 234 and 491 ml/min, respectively, for S-VER and R-VER (Table 1). The fBCLint(cal) values are similar (234 and 491 ml/min versus 260 and 430 ml/min). However, these are not the free CLint values. The CLint values (approximately 1475 ml/min, obtained upon division by fB) relate to the free or unbound drug; fPCLint or fBCLint corrects for the binding in plasma or blood, if there is binding. We acknowledge that we should have compared the CLint estimates at 30 ml/min versus the 1475 ml/min in our recent study (Yang et al., 2015), as shown in Table 1.

In conclusion, our recent article contained a few misquotes and these will be corrected in an erratum. These errors, however, were minor and did not materially detract from the original study design, the elegant physiologically based pharmacokinetic fitting that considered nonlinear metabolism and biliary excretion, and the nonlinear distribution into red cells and protein binding. Most importantly, these minor errors did not affect the authors’ final interpretation of hmi.

Authorship Contributions

Wrote or contributed to the writing of the manuscript: Pang, Yang.

Footnotes

    • Received May 1, 2015.
    • Accepted May 8, 2015.
  • This Letter to the Editor is in response to

  • “Fractional Clearance for Verapamil N-Demethylation in the Isolated Rat Liver Preparation” by Mehvar et al., found in Drug Metab Dispos 2015, 43:1056–1057.

  • dx.doi.org/10.1124/dmd.115.065227.

Abbreviations

CLint
intrinsic clearance
NOR
norverapamil
VER
verapamil
  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics

References

  1. ↵
    1. Mehvar R
    (2015) Letter to the editor: fractional clearance for verapamil N-demethylation in the isolated rat liver preparation. Drug Metab Dispos 43:1056–1057.
    OpenUrl
  2. ↵
    1. Mehvar R and
    2. Reynolds J
    (1996) Reversal of stereoselectivity in the hepatic availability of verapamil in isolated perfused rat livers. Role of protein binding. Drug Metab Dispos 24:1088–1094.
    OpenUrlAbstract
  3. ↵
    1. Mehvar R,
    2. Reynolds JM,
    3. Robinson MA, and
    4. Longstreth JA
    (1994) Enantioselective kinetics of verapamil and norverapamil in isolated perfused rat livers. Pharm Res 11:1815–1819.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Pang KS,
    2. Barker F,
    3. Simard A,
    4. Schwab AJ, and
    5. Goresky CA
    (1995) Sulfation of acetaminophen by the perfused rat liver: the effect of red blood cell carriage. Hepatology 22:267–282.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Pang KS and
    2. Gillette JR
    (1979) Sequential first-pass elimination of a metabolite derived from a precursor. J Pharmacokinet Biopharm 7:275–290.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Pang KS and
    2. Kwan KC
    (1983) A commentary: methods and assumptions in the kinetic estimation of metabolite formation. Drug Metab Dispos 11:79–84.
    OpenUrlPubMed
    1. Pang KS and
    2. Rowland M
    (1977) Hepatic clearance of drugs. I. Theoretical considerations of a “well stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cells binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J Pharmacokinet Biopharm 5:625–653.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Robinson MA and
    2. Mehvar R
    (1996) Enantioselective distribution of verapamil and norverapamil into human and rat erythrocytes: the role of plasma protein binding. Biopharm Drug Dispos 17:577–587.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Yang QJ,
    2. Si L,
    3. Tang H,
    4. Sveigaard HH,
    5. Chow EC, and
    6. Pang KS
    (2015) PBPK modeling to unravel nonlinear pharmacokinetics of verapamil to estimate the fractional clearance for verapamil N-demethylation in the recirculating rat liver preparation. Drug Metab Dispos 43:631–645.
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 43 (7)
Drug Metabolism and Disposition
Vol. 43, Issue 7
1 Jul 2015
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Response to Letter to the Editor on “Fractional Clearance for Verapamil N-Demethylation in the Isolated Rat Liver Preparation”
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
LetterLetter to the Editor

Response to Letter to the Editor

K. Sandy Pang and Qi Joy Yang
Drug Metabolism and Disposition July 1, 2015, 43 (7) 1058-1059; DOI: https://doi.org/10.1124/dmd.115.065227

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
LetterLetter to the Editor

Response to Letter to the Editor

K. Sandy Pang and Qi Joy Yang
Drug Metabolism and Disposition July 1, 2015, 43 (7) 1058-1059; DOI: https://doi.org/10.1124/dmd.115.065227
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Unbound Maximum Hepatic Inlet Concentration
  • Misidentification of Bupropion Glucuronide Metabolites
Show more LETTERS TO THE EDITOR

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics