Prediction of Nonlinear Intestinal Absorption of CYP3A4 and P-Glycoprotein Substrates from their In Vitro Km Values

Tachibana, Tatsuhiko; Kato, Motohiro; Sugiyama, Yuichi

doi:10.1007/s11095-011-0579-2

Cited by 45 publications

(40 citation statements)

References 41 publications

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“…This implies that the normal activity of this enzyme attenuates bioavailability. This effect may be most pronounced at low artemether doses but is saturable at higher doses (32). A formal evaluation of this effect was beyond the scope of the present study, but it may have clinical significance.…”

Section: Discussionmentioning

confidence: 78%

Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults

Salman

Bendel²,

Lee

et al. 2015

Antimicrob Agents Chemother

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Plasma artemether and dihydroartemisinin levels were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In study 1, sublingual artemether absorption was biphasic, with both rate constants being greater than that of the artemether tablets (1.46 and 1.66 versus 0.43/h, respectively). Relative to the tablets, sublingual artemether had greater bioavailability (>1.24), with the greatest relative bioavailability occurring in the 30.0-mg dose groups (>1.58). In study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of the total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism occurring in later versus earlier doses but with no difference in bioavailability between the dose actuations. Sublingual artemether is more rapidly and completely absorbed than are equivalent doses of artemether tablets in healthy adults. Its disposition appears to be complex, with two absorption phases, the first representing pregastrointestinal absorption, as well as dose-dependent bioavailability and autoinduction of metabolism with multiple dosing.

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Section: Discussionmentioning

confidence: 78%

Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults

Salman

Bendel²,

Lee

et al. 2015

Antimicrob Agents Chemother

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“…For example, the relationship between dose-normalised AUC and dose/Km value has been termed the linearity index (LIN). Substrates with a small LIN tend to exhibit linear pharmacokinetics [59]. The combination of pharmacokinetic models and microdosing, particularly in cases where there are significant doubts over the inputs to the models, may prove to be a powerful tool of the future.…”

Section: The Utility Of Microdosingmentioning

confidence: 99%

Microdosing and drug development: past, present and future

Lappin

Noveck²,

Burt

2013

Expert Opinion on Drug Metabolism & Toxicology

115

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Introduction Microdosing is an approach to early drug development where exploratory pharmacokinetic data are acquired in humans using inherently safe sub-pharmacologic doses of drug. The first publication of microdose data was 10 years ago and this review comprehensively explores the microdose concept from conception, over the past decade, up until the current date. Areas covered The authors define and distinguish the concept of microdosing from similar approaches. The authors review the ability of microdosing to provide exploratory pharmacokinetics (concentration-time data) but exclude microdosing using positron emission tomography. The article provides a comprehensive review of data within the peer-reviewed literature as well as the latest applications and a look into the future, towards where microdosing may be headed. Expert opinion Evidence so far suggests that microdosing may be a better predictive tool of human pharmacokinetics than alternative methods and combination with physiologically based modelling may lead to much more reliable predictions in the future. The concept has also been applied to drug-drug interactions, polymorphism and assessing drug concentrations over time at its site of action. Microdosing may yet have more to offer in unanticipated directions and provide benefits that have not been fully realised to date.

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“…Since naringin is reported to be an inhibitor of both P-gp and Oatp1a5 (Shirasaka et al, 2009), the influence of naringin on digoxin absorption was evaluated at the higher concentration (100 lM) of digoxin in this study to minimize the inhibition of P-gp by naringin. As shown in Figure 7, the percentage absorbed at a digoxin concentration of 100 lM increased by approximately 2-fold compared with that at a concentration of 10 lM, and this might be caused by saturation of efflux by P-gp, because the Michaelis constant or half of the maximum inhibitory concentration of digoxin to P-gp reportedly seems to be 26 lM (Tachibana et al, 2012). The inhibition of digoxin transport at a high concentration by naringin implies a mechanism whereby digoxin absorption is mediated by Oatp1a5 in the rat intestine.…”

Section: Discussionmentioning

confidence: 95%

Characterization of gastrointestinal absorption of digoxin involving influx and efflux transporter in rats: application ofmdr1aknockout (−/−) rats into absorption study of multiple transporter substrate

et al. 2014

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1. This study was aimed to characterize gastrointestinal absorption of digoxin using wild-type (WT) and multidrug resistance protein 1a [mdr1a; P-glycoprotein (P-gp)] knockout (-/-) rats. 2. In WT rats, the area under the plasma concentration-time curve (AUC) of oral digoxin increased after oral pretreatment with quinidine at 30 mg/kg compared with non-treatment, but the increasing ratio tended to decrease at a high dose of 100 mg/kg. In mdr1a (-/-) rats, however, quinidine pretreatment caused a dose-dependent decrease in the AUC. 3. Quinidine pretreatment did not alter the hepatic availability of digoxin, indicating that the changes in the digoxin AUC were attributable to inhibition of the absorption process by quinidine; i.e. inhibition of influx by quinidine in mdr1a (-/-) rats and inhibition of efflux and influx by quinidine in WT rats. 4. An in situ rat intestinal closed loop study using naringin implied that organic anion transporting peptide (Oatp) 1a5 may be a responsible transporter in the absorption of digoxin. 5. These findings imply that the rat absorption behavior of digoxin is possibly governed by Oatp1a5-mediated influx and P-gp-mediated efflux. The mdr1a (-/-) rat is therefore a useful in vivo tool to investigate drug absorption associated with multiple transporters including P-gp.

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Prediction of Nonlinear Intestinal Absorption of CYP3A4 and P-Glycoprotein Substrates from their In Vitro Km Values

Abstract: LIN is useful for predicting CYP3A4/P-gp-mediated nonlinearity in intestinal absorption process in humans.

Cited by 45 publications

References 41 publications

Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults

Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults

Microdosing and drug development: past, present and future

Characterization of gastrointestinal absorption of digoxin involving influx and efflux transporter in rats: application ofmdr1aknockout (−/−) rats into absorption study of multiple transporter substrate

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