Dresser GK, Spence JD, Bailey DGPharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 38: 41-57
Department of Medicine, London Health Sciences Centre and The University of Western Ontario, Canada. Clinical Pharmacokinetics
(Impact Factor: 5.05).
02/2000; 38(1):41-57. DOI: 10.2165/00003088-200038010-00003
Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein. Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor. Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir. The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age. Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.
Available from: Robert Shumaker
- "Rifampicin, an antibiotic derivative of rifamycin B, is a strong inducer of P-gp and CYP3A4 upon multiple dosing, but inhibits gut P-gp–mediated transport when only a single dose is administered . At therapeutic doses, rifampicin significantly alters plasma concentrations of CYP3A4 substrates [11–13]. Hence, rifampicin is routinely used to evaluate the potential for drug interactions involving CYP3A4 induction and P-gp induction/inhibition mechanisms with pharmaceutical products including TKIs [14–18]. "
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ABSTRACT: Background and Objectives
Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor under clinical investigation in solid tumours. This study evaluated the influence of P-glycoprotein (P-gp) inhibition (single-dose rifampicin) and simultaneous cytochrome P450 3A4 (CYP3A4)/P-gp induction (multiple-dose rifampicin) on lenvatinib pharmacokinetics.
This Phase I, single-centre, single-dose (lenvatinib mesylate 24 mg), open-label, sequential study enrolled 15 healthy volunteers. Three regimens were administered over three periods: Period (P) 1 (Days 1–8), P2 (Days 15–22) and P3 (Days 29–50), with a 14-day (first dose) and 28-day (second dose) washout period after lenvatinib mesylate administration (Day 1, Day 15 and Day 43). In P2, a single oral dose of rifampicin (600 mg) was coadministered with lenvatinib. In P3, rifampicin was administered daily (600 mg) for 21 days (Days 29–49). Serial blood samples were collected, and plasma concentrations of total (protein bound + unbound) and free (unbound) lenvatinib and total metabolites (M1, M2, M3 and M5) were measured by validated high-performance liquid chromatography/tandem mass spectrometry.
Single-dose rifampicin (P-gp inhibition) increased area under the plasma concentration–time curve from time zero to infinity (AUC0–∞) of free and total lenvatinib by 32 and 31 %, respectively. Multiple-dose rifampicin (simultaneous P-gp and CYP3A4 induction) decreased lenvatinib AUC0–∞ (total: 18 %; free: 9 %). Treatment-emergent adverse events were mild or moderate and occurred in 7 subjects (47 %).
Lenvatinib exposure was increased by P-gp inhibition; however, based on free concentrations, simultaneous P-gp and CYP3A4 induction results met the prespecified bioequivalence 90 % confidence interval. Overall, the magnitude of these changes was relatively small, and likely not clinically meaningful.
Available from: Maja Đanić (Stojančević)
- "Although the concentrations of CYP, normalized for the entire intestine, are estimated to be 20-to 200-fold lower than those found in the liver (Deferme et al., 2008), immunohistochemical studies have shown that small intestinal concentrations of CYP3A4 are approximately 80–100% of the CYP3A4 concentration in the liver (Wacher et al., 2001). Oral pharmacokinetic studies have suggested that the gut wall metabolism of drugs by CYP3A4 has a significant role in total first-pass effect of many drugs (Dresser et al., 2000) such as verapamil (Fromm et al., 1996), midazolam (Thummel et al., 1996), felodipine (Bailey et al., 1991) and cyclosporine (Wu et al., 1995). Of particular importance is the synergistic function of P-glycoprotein (P-gp) and CYP3A4 in the small intestine, which may limit oral drug bioavailability of a wide variety of compounds (Martinez and Amidon, 2002). "
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ABSTRACT: Although the liver has long been considered as a main organ responsible for drug metabolism, the role of the gut metabolizing enzymes and the gut microflora is becoming more profoundly evident in drug metabolism, absorption and overall efficacy. This review will explore various mechanisms by which the gut-microflora influences drug pharmacokinetics including biotransformation, bioactivation, and biodegradation as well as up- or down-regulation of the epithelial transporters. The gut-luminal fluids, intestinal mucosa and gut microflora contain high concentrations of various enzymes which are responsible for the oxidation, hydrolysis and conjugation of drugs. Such metabolic reactions may lead to either drug over or underdosing, which impacts the drugs efficacy and safety. The processes, by which the intestinal enzymes and gut-protein transporters influence drug pharmacokinetic parameters, will be detailed. Since the intestinal microflora plays an important role in physiological, nutritional, metabolic, and immunological processes in human body, there is currently some interest in the manipulation of its composition and activity by administering probiotics. This review will also examine the capacity of probiotics to interact with resident microbial community, affecting the respective enzymes or by providing their own specific enzymatic activities that may consequently change the bioavailability and pharmacological activity of concomitantly taken drugs.
Available from: Michael Noel Neely
- "Daily 0.35 mg of norethindrone (NET) is administered as a continuous oral contraceptive in US progestin-only pills. The half-life of NET is 8–12 hours, and its peak plasma concentration occurs within 2 hours of oral ingestion.11 Hydroxylation of NET to its M1 metabolite is predominately due to CYP3A4 catalyzed reactions in the liver and to a lesser degree in the small intestine.11,15 "
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ABSTRACT: Pharmacokinetic interactions exist between combined oral contraceptives and protease inhibitors (PI). However, such information is lacking for progestin-only oral contraception. We sought to define the steady-state pharmacokinetic interaction between norethindrone (NET) and PI in HIV infected women.
We conducted an open-label, prospective, non-randomized trial to characterize the steady-state pharmacokinetics of serum NET in HIVinfected women receiving PI compared to a control group of HIVinfected women receiving other non interacting drugs. Following 21 days of NET 0.35 mg ingestion once daily, serial serum samples were obtained at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours. The area under the curve between 0 and 72 hours after ingestion was calculated by trapezoidal approximation.
Thirty-five women were enrolled, two withdrew. Sixteen women in the PI group and 17 controls completed the study. NET half life, and maximum concentration were not significantly different between the two groups. Minimum concentration of NET was significantly higher in the PI group (p=0.01). The ratio of the geometric mean NET area under the curve in the PI group compared to controls was 1.5 (90% confidence interval 1.21-1.86). NET serum concentrations are significantly higher in HIVinfected women taking a PI compared to controls (p=0.004).
Co-administration of PI inhibits NET metabolism as shown by higher serum NET area under the curve levels, a surrogate marker for therapeutic contraceptive efficacy. This study supports increased utilization of progestin only pills in HIV infected women receiving certain PI regimens.
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