Pharmacokinetics Of Probe Drugs Research Articles

Probe drug T-1032 N-oxygenation mediated by cytochrome P450 3A5 in human hepatocytes in vitro and in humanized-liver mice in vivo

Polymorphic cytochrome P450 3A5 (CYP3A5) expression contributes to individual differences in the pharmacokinetics of probe drugs. The identification of suitable in vivo CYP3A5 probes would benefit drug metabolism and drug interaction studies using chimeric mice with humanized liver. In this study, we investigated the pharmacokinetic profiles of T-1032, which is known as an in vitro CYP3A5 probe substrate, using humanized-liver mice. Substantial N-oxygenation of T-1032 was observed in hepatocytes from humans and from humanized-liver mice. Hepatocytes from the human donor genotyped as CYP3A5∗3/∗3 (poor expressers) showed significantly lower T-1032 N-oxidation rates than those from donors harboring CYP3A5∗1. After a single oral dose of T-1032 (1.0 mg/kg) in humanized-liver mice, the plasma levels of T-1032 N-oxide were higher in five mice with CYP3A5∗1/∗7 hepatocytes than in four mice with CYP3A5∗3/∗3 hepatocytes. The maximum concentrations of T-1032 N-oxide after oral administration of T-1032 in humanized-liver mice with CYP3A5∗1/∗7 hepatocytes were twice (a significant difference) those from humanized-liver mice with CYP3A5∗3/∗3 hepatocytes. These results suggest that polymorphic CYP3A5-dependent T-1032 N-oxidation was observed in humanized liver mice in vitro and in vivo. However, the contribution of CYP3A5 genotypes may have little or only limited effects on the overall pharmacokinetic profiles of T-1032 in vivo.

The effect of obesity, macronutrients, fasting and nutritional status on drug-metabolizing cytochrome P450s: a systematic review of current evidence on human studies.

Cytochrome P450s (CYPs) are a class of hemoproteins involved in drug metabolism. It has been reported that body composition, proportion of dietary macronutrients, fasting and nutritional status can interfere with the activity of drug-metabolizing CYPs. The present systematic review was conducted to summarize the effect of obesity, weight reduction, macronutrients, fasting and malnutrition on the CYP-mediated drug metabolism. PubMed (Medline), Scopus, Embase and Cochrane Library databases and Google Scholar were searched up to June 2020 to obtain relevant studies. The PRISMA guidelines were employed during all steps. Two reviewers independently extracted the information from the included studies. Studies investigating CYPs activity directly or indirectly through pharmacokinetics of probe drugs, were included. Increase in clearance (CL) or decrease in elimination half-life (t½) and area under the curve (AUC) of probe drugs were considered as increase in CYPs activity. A total of 6545 articles were obtained through searching databases among which 69 studies with 126 datasets fully met the inclusion criteria. The results indicated that obesity might decrease the activity of CYP3A4/5, CYP1A2 and CYP2C9 and increase the activity of CYP2E1. The effect of obesity on CYP2D6 is controversial. Also, weight loss increased CYP3A4 activity. Moreover, CYP1A2 activity was decreased by high carbohydrate diet, increased by high protein diet and fasting and unchanged by malnutrition. The activity of CYP2C19 was less susceptible to alterations compared to other CYPs. The activity of drug-metabolizing CYPs are altered by body composition, dietary intake and nutritional status. This relationship might contribute to drug toxicity or reduce treatment efficacy and influence cost-effectiveness of medical care.

Short-Term Fasting Alters Pharmacokinetics of Cytochrome P450 Probe Drugs: Does Protein Binding Play a Role?

Background and ObjectivesShort-term fasting differentially alters cytochrome P450 (CYP) mediated drug metabolism. This has been established by using CYP-enzyme selective probe drugs. However, the observed effects of fasting on the pharmacokinetics of these probe drugs may also include the effects of altered plasma protein binding of these drugs. Therefore, we studied the effect of short-term fasting on protein binding of five commonly used probe drugs [caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and S-warfarin (CYP2C9)].MethodsThe free and total plasma concentrations of the five probe drugs were analyzed by LC–MS/MS in samples retrieved in a cross-over study in which nine healthy subjects received an intravenous administration of the cocktail after an overnight fast (control) and after 36 h of fasting.ResultsShort-term fasting increased plasma free fatty acid concentrations from 0.48 mmol/L (control) to 1.29 mmol/L (36 h fasting) (p = 0.012). Short-term fasting did not alter the free fractions of caffeine, metoprolol and omeprazole compared to the control intervention (p > 0.05). Power to detect a difference for midazolam and S-warfarin was low since the majority of free concentrations were below the limit of quantification.ConclusionsThis study demonstrates that short-term fasting does not alter protein binding of the probe drugs caffeine, metoprolol and omeprazole.Electronic supplementary materialThe online version of this article (doi:10.1007/s13318-017-0437-7) contains supplementary material, which is available to authorized users.

Abstract C85: Drug interaction study of tivantinib in cancer subjects using a cocktail approach.

Abstract Background: Tivantinib (ARQ197) is an orally administered cMET inhibitor currently under development as a cancer therapy. Nonclinical studies have indicated that tivantinib and its major metabolites have the potential to inhibit cytochrome P450 (CYP) 3A4, 2C19, 2C9, and 1A, and the P-glycoprotein (P-gp) at the clinical concentrations being studied in phase 3 studies. The objective of this drug interaction study was to assess the effect of tivantinib at steady state levels on the pharmacokinetics of CYP- and P-gp-specific probe drugs (modified Cooperstown 5 + 1 Cocktail) after multiple BID doses of tivantinib. Methods: This was a phase 1, open-label, single-sequence, crossover study (NCT01517399) in subjects with advanced solid tumors. Each subject was administered five probe drugs in the absence or presence of tivantinib (360 mg BID): midazolam (CYP3A4), omeprazole (CYP2C19), S-warfarin (CYP2C9), caffeine (CYP1A), and digoxin (P-gp). Serial blood samples were collected to determine the pharmacokinetics of the probe drugs. Pharmacokinetic parameters were computed using a non-compartmental approach. Log-transformed pharmacokinetic parameters were analyzed using a linear mixed-effects model with treatment as fixed effects and subject as a random effect, and the ratio of geometric least-square (LS) means and the 90% CI for test treatment (Probe drug administered with tivantinib) to reference treatment (probe drug administered alone) were calculated. No drug interaction was concluded if the 90% CI of the LS mean ratios are within the range of 0.8-1.25. Results: Twenty eight cancer subjects were enrolled. The ratios of geometric LS mean (90% CI) for total exposure parameter (AUClast) were as follows: midazolam, 0.83 (0.67, 1.02); omeprazole, 0.89 (0.60, 1.31); S[[Unable to Display Character: ‑]]warfarin, 0.88 (0.76, 1.02); caffeine, 0.97 (0.89, 1.05); and digoxin, 0.69 (0.51, 0.94). Small changes in exposure were observed for midazolam, omeprazole, and warfarin with AUClast decreased ∼17%. Consistent with decrease in omeprazole AUClast (∼11.1%), the mean omeprazole/5-hydroxyomeprazole AUC ratio decreased by 12.8%. For digoxin, mean AUClast decreased by 30.9%. No interaction was determined on the caffeine pharmacokinetics. The effect on peak exposures (Cmax) was similar to the effect on AUClast. Treatment with tivantinib in combination with probe drugs omeprazole/warfarin/caffeine/midazolam or digoxin was generally well tolerated. Conclusion: These results suggested that coadministration of tivantinib 360 mg BID has a small or no effect on the pharmacokinetics of probe drugs used in this study. It is likely that the observed effect of tivantinib on CYP1A2, CYP2C9, CYP2C19, CYP3A4 and P-gp is of minimal clinical significance. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C85. Citation Format: Masaya Tachibana, Kyriakos P. Papadopoulos, John Strickler, Igor Puzanov, Roohi Gajee, Yibin Wang, Hamim Zahir. Drug interaction study of tivantinib in cancer subjects using a cocktail approach. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C85.