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Clinical Pharmacokinetics

Erschienen in:

28.07.2020 | Original Research Article

Volume of Distribution is Unaffected by Metabolic Drug–Drug Interactions

verfasst von: Jasleen K. Sodhi, Caroline H. Huang, Leslie Z. Benet

Erschienen in: Clinical Pharmacokinetics | Ausgabe 2/2021

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Abstract

Introduction

It has been recognized that significant transporter interactions result in volume of distribution changes in addition to potential changes in clearance. For drugs that are not clinically significant transporter substrates, it is expected that drug–drug interactions would not result in any changes in volume of distribution.

Methods

An evaluation of this hypothesis proceeded via an extensive analysis of published intravenous metabolic drug–drug interactions, based on clinically recommended index substrates and inhibitors of major cytochrome P450 (CYP) isoforms.

Results

Seventy-two metabolic drug interaction studies were identified where volume of distribution at steady-state (V_ss) values were available for the CYP index substrates caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), theophylline (CYP1A2), and tolbutamide (CYP2C9). Changes in exposure (area under the curve) up to 5.1-fold were observed; however, ratios of V_ss changes have a range of 0.70–1.26, with one outlier displaying a V_ss ratio of 0.57.

Discussion

These results support the widely held founding tenant of pharmacokinetics that clearance and V_ss are independent parameters. Knowledge that V_ss is unchanged in metabolic drug–drug interactions can be helpful in discriminating changes in clearance from changes in bioavailability (F) when only oral dosing data are available, as we have recently demonstrated. As V_ss remains unchanged for intravenous metabolic drug–drug interactions, following oral dosing changes in V_ss/F will reflect changes in F alone. This estimation of F change can subsequently be utilized to assess changes in clearance alone from calculations of apparent clearance. Utilization of this simple methodology for orally dosed drugs will have a significant impact on how drug–drug interactions are interpreted from drug development and regulatory perspectives.

Grover A, Benet LZ. Effects of drug transporters on volume of distribution. AAPS J. 2009;11:250–61.PubMedPubMedCentralCrossRef

Benet LZ, Bowman CM, Sodhi JK. How transporters have changed basic pharmacokinetic understanding. AAPS J. 2019;21:103.PubMedCrossRef

Sodhi JK, Benet LZ. A simple methodology to differentiate changes in bioavailability from changes in clearance following oral dosing of metabolized drugs. Clin Pharmacol Ther. 2020;108:306–15.PubMedCrossRef

Tornio A, Filppula AM, Niemi M, Backman JT. Clinical studies on drug–drug interactions involving metabolism and transport: methodology, pitfalls and interpretation. Clin Pharmacol Ther. 2019;105:1345–61.PubMedPubMedCentralCrossRef

Isoherranen N, Lutz JD, Chung SP, Hachad H, Levy RH, Ragueneau-Majlessi I. Importance of multi-P450 inhibition in drug–drug interactions: evidence of incidence, inhibition magnitude, and prediction from in vitro data. Chem Res Toxicol. 2012;25:2285–300.PubMedPubMedCentralCrossRef

Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin. Clin Pharmacokinet. 2003;42:819–50.PubMedCrossRef

Pelkonen O, Mäeenpäeä J, Taavitsainen P, Rautio A, Paunio H. Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica. 1998;28:1203–53.PubMedCrossRef

Pelkonen O, Turpeinen M, Hakkola J, Honkakoski P, Hukkanen J, Raunio H. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008;82:667–715.PubMedCrossRef

Polasek TM, Lin FPY, Miners JO, Doogue MP. Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity: a criteria-based assessment. Br J Clin Pharmacol. 2011;71:727–36.PubMedPubMedCentralCrossRef

10.

Bi Y, Mathialagan S, Tylaska L, Fu M, Keefer J, Vildede A, et al. Organic anion transporter 2 mediates hepatic uptake of tolbutamide, a CYP2C9 probe drug. J Pharmacol Exp Ther. 2018;364:390–8.PubMedCrossRef

11.

Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT. Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin Pharmacol Toxicol. 2005;97:249–56.PubMedCrossRef

12.

Wu C-Y, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22:11–23.PubMedCrossRef

13.

Benet LZ, Galeazzi RL. Noncompartmental determination of the volume of distribution steady state. J Pharm Sci. 1979;68:1071–4.PubMedCrossRef

14.

Wahlländer A, Paumgartner G. Effect of ketoconazole and terbinafine on the pharmacokinetics of caffeine in healthy volunteers. Eur J Clin Pharmacol. 1989;37:279–83.PubMedCrossRef

15.

Leemann TD, Devi KP, Dayer P. Similar effect of oxidation deficiency (debrisoquine polymorphism) and quinidine on the apparent volume of distribution of (±)-metoprolol. Eur J Clin Pharmacol. 1993;45:65–71.PubMedCrossRef

16.

Gorski JC, Jones DR, Haehner-Daniels BD, Hamman MA, O’Mara EM, Hall SD. The contribution of intestinal and hepatic CYP3A4 to the interaction between midazolam and clarithromycin. Clin Pharmacol Ther. 1998;64:133–43.PubMedCrossRef

17.

Quinney SK, Haehner BD, Rhoades MB, Lin Z, Gorski JC, Hall SD. Interaction between midazolam and clarithromycin in the elderly. Br J Clin Pharmacol. 2008;65:98–109.PubMedCrossRef

18.

Olkkola KT, Aranko K, Luurila H, Hiller A, Saarnivarra L, Himberg JJ, Neuvonen PJ. A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther. 1993;53:298–305.PubMedCrossRef

19.

Swart EL, van der Hoven B, Groeneveld ABJ, Touw DJ, Danhof M. Correlation between midazolam and lignocaine pharmacokinetics and MEGX formation in healthy volunteers. Br J Clin Pharmacol. 2002;53:133–9.PubMedPubMedCentralCrossRef

20.

Kharasch ED, Walker A, Hoffer C, Sheffels P. Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimally invasive and noninvasive probes for hepatic and first-pass CYP3A activity. J Clin Pharmacol. 2005;45:1187–97.PubMedCrossRef

21.

Isoherranen N, Ludington SR, Givens RC, Lamba JK, Pusek SN, Dees EC, et al. The influence of CYP3A5 expression on the extent of hepatic CYP3A inhibition is substrate-dependent: an in vitro-in vivo evaluation. Drug Metab Dispos. 2008;36:146–54.PubMedCrossRef

22.

Olkkola KT, Ahonen J, Neuvonen PJ. The effect of systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg. 1996;82:511–6.PubMed

23.

Tsunoda SM, Velez RL, von Moltke LL, Greenblatt DJ. Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Clin Pharmacol Ther. 1999;66:461–71.PubMedCrossRef

24.

Shin K-H, Ahn LY, Choi MH, Moon J-Y, Lee J, Jang I-J, et al. Urinary 6β-hydroxycortisol/cortisol ratio most highly correlates with midazolam clearance under hepatic CYP3A inhibition and induction in females: a pharmacometabolomics approach. AAPS J. 2016;18:1254–61.PubMedCrossRef

25.

Kirby BJ, Collier AC, Kharasch ED, Whittington D, Thummel KE, Unadkat JD. Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir. Drug Metab Dispos. 2011;38:1070–8.CrossRef

26.

Loi C-M, Parker BM, Cusak BJ, Vestal RE. Aging and drug interactions. III. Individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism in healthy male and female nonsmokers. J Pharmacol Exp Ther. 1997;280:627–37.PubMed

27.

Breen KJ, Bury R, Desmond MB, Mashford MB, Morphett B, Westwood B, et al. Effects of cimetidine and ranitidine on hepatic drug metabolism. Clin Pharmacol Ther. 1982;31:297–300.PubMedCrossRef

28.

Gugler R, Wolf M, Hansen H-H, Jensen JC. The inhibition of drug metabolism by cimetidine in patients with liver cirrhosis. Klin Wochenschr. 1984;62:1126–31.PubMedCrossRef

29.

Jackson JE, Powell JR, Wandell M, Bentley J, Dorr R. Cimetidine decreases theophylline clearance. Am Rev Respir Dis. 1981;123:615–7.PubMed

30.

Lin JH, Chremos AN, Chiou R, Yeh KC, Williams R. Comparative effect of famotidine and cimetidine on the pharmacokinetics of theophylline in normal volunteers. Br J Clin Pharmacol. 1987;24:669–72.PubMedPubMedCentralCrossRef

31.

Macias WL, Bergstrom RF, Cerimele BJ, Kassahun K, Tatum DE, Callagan JT. Lack of effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men. Pharmacotherapy. 1998;18:1237–48.PubMed

32.

Bachmann K, Sullivan TJ, Reese JH, Jauregui L, Miller K, Scott M, et al. Controlled study of the putative interaction between famotidine and theophylline in patients with chronic obstructive pulmonary disease. J Clin Pharmacol. 1995;35:529–35.PubMedCrossRef

33.

Davis RL, Quenzer RW, Kelly HW, Powell JR. Effect of the addition of ciprofloxacin on theophylline pharmacokinetics in subjects inhibited by cimetidine. Ann Pharmacother. 1992;26:11–3.PubMedCrossRef

34.

Prince RA, Casabar E, Adair CG, Wexler DB, Lettieri J, Kasik JE. Effect of quinolone antimicrobials on theophylline pharmacokinetics. J Clin Pharmacol. 1989;29:650–4.PubMedCrossRef

35.

Abernethy DR, Egan JM, Dickinson TH, Carrum G. Substrate-selective inhibition by verapamil and diltiazem: differential disposition of antipyrine and theophylline in humans. J Pharmacol Exp Ther. 1988;224:994–9.

36.

Sano M, Kawakatsu K, Ohkita C, Yamamoto I, Takeyama M, Yamashina H, Goto M. Effects of enoxacin, ofloxacin and norfloxacin on theophylline disposition in humans. Eur J Clin Pharmacol. 1988;35:161–5.PubMedCrossRef

37.

Stringer KA, Mallet J, Clarke M, Lindenfeld JA. The effect of three different oral doses of verapamil on the disposition of theophylline. Eur J Clin Pharmacol. 1992;43:35–8.PubMedCrossRef

38.

Nielsen-Kudsk JE, Buhl JS, Johannessen AC. Verapamil-induced inhibition of theophylline elimination in healthy humans. Pharmacol Toxicol. 1990;66:101–3.PubMedCrossRef

39.

Back DJ, Tjia J, Mönig H, Ohnhaus EE, Park BK. Selective inhibition of drug oxidation after simultaneous administration of two probe drugs, antipyrine and tolbutamide. Eur J Clin Pharmacol. 1988;34:157–63.PubMedCrossRef

40.

Roberts RK, Grice J, Wood L, Petroff V, McGuffie C. Cimetidine impairs the elimination of theophylline and antipyrine. Gastroenterology. 1981;81:19–21.PubMedCrossRef

41.

Ciraulo DA, Barnhill J, Boxenbaum H. Pharmacokinetic interaction of disulfiram and antidepressants. Am J Psychiatry. 1985;142:1373–4.PubMedCrossRef

42.

Cremer KF, Secor J, Speeg KV Jr. The effect of route of administration on the cimetidine–theophylline drug interaction. J Clin Pharmacol. 1989;29:451–6.PubMedCrossRef

43.

Loi C-M, Parker BM, Cusack BJ, Vestal RE. Individual and combined effects of cimetidine and ciprofloxacin on theophylline metabolism in male nonsmokers. Br J Clin Pharmacol. 1993;36:195–200.PubMedPubMedCentralCrossRef

44.

Prince RA, Wing DS, Weinberger MM, Hendeles LS, Riegelman S. Effects of erythromycin on theophylline kinetics. J Allergy Clin Immunol. 1981;68:427–31.PubMedCrossRef

45.

Benet LZ, Bowman CM, Koleske ML, Rinaldi CL, Sodhi JK. Understanding drug–drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs. J Pharmacokinet Pharmacodyn. 2019;42:155–63.CrossRef

Titel: Volume of Distribution is Unaffected by Metabolic Drug–Drug Interactions
verfasst von: Jasleen K. Sodhi
Caroline H. Huang
Leslie Z. Benet
Publikationsdatum: 28.07.2020
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 2/2021
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-020-00926-7

Springer Medizin

Abstract

Introduction

Methods

Results

Discussion

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