Differentiation of organ availability by sequential and simultaneous analyses: Intestinal conjugative metabolism impacts on intestinal availability in humans

doi:10.1002/jps.20269

Journal of Pharmaceutical Sciences

Volume 94, Issue 3, March 2005, Pages 571-575

https://doi.org/10.1002/jps.20269 Get rights and content

Abstract

The impact of intestinal conjugative metabolism on oral bioavailability was assessed by sequential and simultaneous analyses of the reported data in humans. The data were retrieved from reports on drugs that are metabolized by sulfate conjugation, and the organ availabilities affecting oral bioavailability were differentiated. Sequential analysis gave the following results. The intestinal availability (Fg) of salbutamol was 0.700, whereas hepatic availability (Fh) and bioavailability (F) were 0.893 and 0.493, respectively. Fg of (+)‐terbutaline, (−)‐terbutaline, and (±)‐terbutaline was 0.128, 0.254, and 0.250, respectively. In contrast, Fh of (+)‐terbutaline, (−)‐terbutaline, and (±)‐terbutaline was 0.979, 0.971, and 0.946, respectively. Fg and Fh of ethynylestradiol were 0.536 and 0.780, respectively. Simultaneous analysis also gave similar results, although the sequential analysis overestimated the intestinal availability. These results indicate that intestinal sulfation metabolism has more impact on intestinal availability than on hepatic availability, resulting in low bioavailability in humans. © 2005 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:571–575, 2005

Section snippets

INTRODUCTION

Orally administered drugs must pass through three key processes to enter the systemic circulation.¹ These processes are: the fraction entering the tissue (Ff), which is the fraction neither lost in the feces nor decomposed in the lumen; the fraction escaping destruction (metabolism) within the walls of the gastrointestinal tract (Fg); and the fraction escaping liver extraction (Fh). Although Ff and Fh have been recognized as primary factors in bioavailability (F), Fg has not. Now, however,

Sequential Analysis

Hepatic clearance (CLh) is obtained by eqs. 1 and 2²,³. $CLh = CLm$ $= CLt - CLr$ where CLm, CLt, and CLr are metabolic clearance in the body, total body clearance, and renal clearance, respectively. $CLt = Div/AUCiv$ $Fh = 1 - CLh/Qh$ $F = (AUCpo/Dpo) / (AUCiv/Div)$ $Fg = F/ (Ff \times Fh)$ where Fh and Fg are hepatic availability and intestinal availability, respectively, obtained by sequential analysis. Div and Dpo are intravenous and oral dose, respectively. AUCiv and AUCpo are under the concentration curve of the drug after

Salbutamol

Fg and Fh, which were obtained by sequential and simultaneous analyses, are shown in Table 1, together with related parameters. The total body clearance (CLt), renal clearance (CLr), and bioavailability (F) of salbutamol in volunteers were from the report of Morgan et al.⁸ Ff was calculated by dividing the amount of urinary salbutamol and sulfate conjugate by the oral dose. Sequential analysis gave Fg of 0.700 and Fh of 0.893. Fg was lower than Fh, indicating that intestinal sulfation

REFERENCES (17)

T. Mizuma et al.
Inhibitory effect of phloridzin and phloretin on glucuronidation of p‐nitrophenol, acetaminophen and 1‐naphthol: Kinetic demonstration of the influence of glucuronidation metabolism on intestinal absorption in rats
Biochim Biophys Acta
(1998)
D.J. Back et al.
The pharmacokinetics of a large (3 mg) oral dose of ethynylestradiol in women
Contraception
(1980)
T. Mizuma
Kinetic impact of presystemic intestinal metabolism on drug absorption: Experiment and data analysis for the prediction of in vivo absorption from in vitro data
Drug Metab Pharmacokinet
(2002)
L. Hulten et al.
Sympathetic nervous control of intramural blood flow in the feline and human intestines
Gastroenterology
(1977)
D.J. Back et al.
An investigation of the pharmacokinetics of ethynylestradiol in women using radioimmunoassay
Contraception
(1979)
M. Rowland et al.
Clinical pharmacokinetics. Concept and applications
(1995)
C.‐.Y. Wu et al.
Differentiation of absorption and first‐pass gut and hepatic metabolism in humans: Studies with cyclosporine
Clin Pharmacol Ther
(1995)
K.E. Thummel et al.
Oral first‐pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A‐mediated metabolism
Clin Pharmacol Ther
(1996)

There are more references available in the full text version of this article.

Cited by (15)

Quantitative prediction of intestinal glucuronidation of drugs in rats using in vitro metabolic clearance data
2012, Drug Metabolism and Pharmacokinetics
UDP-glucuronosyltransferase (UGT) is highly expressed in the small intestine and catalyzes the glucuronidation of small molecules, which may affect the oral bioavailability of drugs. However, no method of predicting the in vivo observed fraction of absorbed drug (F_aF_g) affected by UGT has yet been established. Here, we investigated the relationship between F_aF_g and in vitro clearance of nine UGT substrates (ketoprofen, tolcapone, telmisartan, raloxifene, entacapone, resveratrol, buprenorphine, quercetin, and ezetimibe) via UGT in intestinal microsomes (CL_int,_UGT) in rats. F_aF_g was calculated from pharmacokinetic parameters after intravenous and oral administration or using the portal-systemic concentration difference method, with values ranging from 0.027 (ezetimibe) to 1 (tolcapone). Glucuronides of model compounds were observed in the portal plasma after oral administration, with CL_int,_UGT values ranging from 57.8 (tolcapone) to 19,200 μL/min/mg (resveratrol). An inverse correlation between F_aF_g and CL_int,_UGT was observed for most compounds and was described using a simplified intestinal availability model reported previously. This model gave accurate predictions of F_aF_g values for three in-house compounds. Our results show that FaFg in rats is affected by UGT and can be predicted using CL_int,UGT. This work should hasten the development of a method to predict F_aF_g in humans.
Assessment of presystemic and systemic intestinal availability of orally administered drugs using in vitro and in vivo data in humans: Intestinal sulfation metabolism impacts presystemic availability much more than systemic availability of salbutamol, SULT1A3 substrate
2008, Journal of Pharmaceutical Sciences
Citation Excerpt :
Considering that the blood flow rate of the intestine is approximately two thirds that of the liver and one fifth that of the lung, the higher intrinsic clearance from the intestine than from the liver caused the most impact of the intestine on systemic availability among metabolic organs. In the previous study, organ availability was assessed using two different analyses (sequential and simultaneous analyses) using only in vivo data,9 which assumed the following. First, sequential analysis assumed that no organs other than the liver contribute to total body clearance.
Although hepatic availability has been extensively studied to assess the oral bioavailability of drugs, intestinal availability has not, especially that related to conjugative metabolism (phase II metabolism). The present study assessed intestinal presystemic availability by integrating the reported metabolism data in vitro and in vivo of salbutamol, SULT1A3 substrate, in humans. Intrinsic clearance from each organ was calculated with the reported kinetic parameters for salbutamol sulfation metabolism in vitro. Then, presystemic (except intestine) and systemic organ availability and organ clearance were estimated by scaling up the in vitro data using biochemical and physiological data. Scaling factors used were one third, one and three times. Intestinal presystemic availability was calculated without assumptions of a well‐stirred model. Presystemic availability of the intestine is much lower than systemic availability of the intestine. In addition, presystemic availability of the intestine is lower than presystemic availability of other organs, the liver or lung. SULT1A3 is expressed primarily in the intestine; therefore, it should be noted that intestinal metabolism affects the oral bioavailability of drugs, which are metabolized by SULT1A3. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci
Clinical pharmacokinetics of terbutaline in humans: a systematic review
2023, Naunyn-Schmiedeberg's Archives of Pharmacology
Identification of Human UDP-Glucuronosyltransferase and Sulfotransferase as Responsible for the Metabolism of Dotinurad, a Novel Selective Urate Reabsorption Inhibitor<sup>S</sup>
2021, Drug Metabolism and Disposition
Protein Abundance of Clinically Relevant Drug-Metabolizing Enzymes in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens
2018, Clinical Pharmacology and Therapeutics
Efficiency of Ipratropium Bromide and Albuterol Deposition in the Lung Delivered via a Soft Mist Inhaler or Chlorofluorocarbon Metered-Dose Inhaler
2016, Clinical and Translational Science

View all citing articles on Scopus

^*: This study was presented in part as a report in the poster session, and as a selected paper for oral presentation (Chairs: Dr. Chong‐Kook Kim and Dr. Vinod P. Shah), at the Pharmaceutical Sciences World Congress 2004 in Kyoto (May 29–June 3, 2004).

View full text

Article preview

Journal of Pharmaceutical Sciences

Abstract

Section snippets

INTRODUCTION

Sequential Analysis

Salbutamol

REFERENCES (17)

Inhibitory effect of phloridzin and phloretin on glucuronidation of p‐nitrophenol, acetaminophen and 1‐naphthol: Kinetic demonstration of the influence of glucuronidation metabolism on intestinal absorption in rats

Biochim Biophys Acta

The pharmacokinetics of a large (3 mg) oral dose of ethynylestradiol in women

Contraception

Kinetic impact of presystemic intestinal metabolism on drug absorption: Experiment and data analysis for the prediction of in vivo absorption from in vitro data

Drug Metab Pharmacokinet

Sympathetic nervous control of intramural blood flow in the feline and human intestines

Gastroenterology

An investigation of the pharmacokinetics of ethynylestradiol in women using radioimmunoassay

Contraception

Clinical pharmacokinetics. Concept and applications

Differentiation of absorption and first‐pass gut and hepatic metabolism in humans: Studies with cyclosporine

Clin Pharmacol Ther

Oral first‐pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A‐mediated metabolism

Clin Pharmacol Ther

Cited by (15)

Quantitative prediction of intestinal glucuronidation of drugs in rats using in vitro metabolic clearance data

Assessment of presystemic and systemic intestinal availability of orally administered drugs using in vitro and in vivo data in humans: Intestinal sulfation metabolism impacts presystemic availability much more than systemic availability of salbutamol, SULT1A3 substrate

Clinical pharmacokinetics of terbutaline in humans: a systematic review

Identification of Human UDP-Glucuronosyltransferase and Sulfotransferase as Responsible for the Metabolism of Dotinurad, a Novel Selective Urate Reabsorption Inhibitor<sup>S</sup>

Protein Abundance of Clinically Relevant Drug-Metabolizing Enzymes in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens

Efficiency of Ipratropium Bromide and Albuterol Deposition in the Lung Delivered via a Soft Mist Inhaler or Chlorofluorocarbon Metered-Dose Inhaler

Research ArticlesDifferentiation of organ availability by sequential and simultaneous analyses: Intestinal conjugative metabolism impacts on intestinal availability in humans*

Abstract

Section snippets

INTRODUCTION

Sequential Analysis

Salbutamol

Biochim Biophys Acta

Contraception

Drug Metab Pharmacokinet

Gastroenterology

Contraception

Clinical pharmacokinetics. Concept and applications

Differentiation of absorption and first‐pass gut and hepatic metabolism in humans: Studies with cyclosporine

Clin Pharmacol Ther

Oral first‐pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A‐mediated metabolism

Clin Pharmacol Ther

Research Articles
Differentiation of organ availability by sequential and simultaneous analyses: Intestinal conjugative metabolism impacts on intestinal availability in humans*