Direct oral anticoagulants (DOACs) drug-to-drug interactions are underrecognized by clinicians. Apixaban has cytochrome 450 (CYP) mediated metabolism (primarily by CYP3A4). Strong inducers and inhibitors of this enzyme may cause variations in the blood level of apixaban. This report presents a patient who received a femoral artery stent and developed a large retroperitoneal hemorrhage after she was prescribed apixaban in addition to her antiretroviral therapy (AVT) regimen that included cobicistat, a strong CYP3A4 inhibitor. The patient was managed conservatively, and a repeat computed tomography scan in a subsequent admission revealed near resolution of the hematoma. The treating physicians realized that apixaban should not be prescribed with a potent CYP3A4 inhibitor like cobicistat and discontinued it.

Couple of ethnopharmacological surveys in the Indian Ladakh and Pakistani Shigar valleys has reported the medicinal use of Acantholimon lycopodioides against cardiac and gastric disorders that however, remains without scientific rationale or experimental validations. Here, we assess the in vitro bio/therapeutic activities of A. lycopodioides extracts as well as chloroform, ethyl acetate, n-butanol and aqueous fractions. The in vitro β-carotene-linoleic acid bleaching and DPPH radical scavenging methods demonstrated a very high anti-oxidative property of chloroform and ethyl acetate fractions compared to others. Cell viability assay (MTT) on human cervical (HeLa), breast (MDA-MB321) and liver (HepG2) cancer cells revealed their differential cytotoxicity, except the chloroform fraction. Of these, the precipitate exerted highest cytotoxicity on HepG2 cells followed by aqueous fraction on MDA-MB321 cells. Notably, the non-cytotoxicity of chloroform fraction coincided with its highest anti-oxidative activity. Further, the chloroform fraction showed marked hepatoprotection (up to 84%) against 3\'7\'dichlorofluorescin triggered free radicals induced oxidative damage. Also, the hepatoprotective chloroform fraction mildly activated CYP3A4 in HepG2 cells (dual-luciferase assay). Moreover, the A. lycopodioides extracts and fractions showed differential anti-bacterial and anti-fungal activities. Of these, while S. aureus was more sensitive to the water-insoluble extract, ethyl acetate fraction showed moderate activity against E. coli and C. albicans. On the other hand, the chloroform fraction showed promising activity against S. Aureus, C. albicans, P. vulgaris and E. faecalis. In conclusion, our data for the first time, demonstrated promising anti-oxidative, hepatoprotective, anti-cancer, anti-microbial and CYP3A4 activating salutations of A. lycopodioides. This warrants further studies towards isolation and identification of its therapeutically active principles.

BACKGROUND: Metoclopramide is metabolized by various cytochrome P450 (CYP) enzymes such as CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. Rifampicin is a non-selective inducer of P-glycoprotein (P-gp) and CYP enzymes such as CYP3A4 and others.
OBJECTIVE: This study was aimed at the evaluation of rifampicin\'s enzyme induction effect on the pharmacokinetic parameters of orally administered metoclopramide.
METHODS: This randomized, single-blind, two-phase cross-over pharmacokinetic study separated by a 4-week washout period was conducted at a single center in Pakistan. It involved twelve Pakistani healthy male volunteers (nonsmokers) divided into two groups. In the reference phase, each volunteer received a single oral dose of 20 mg metoclopramide (Maxolon 10 mg, GlaxoSmithKline, Pakistan), while in the rifampicin-treated phase, each volunteer received 600 mg rifampicin once daily for 6 days through oral route. On day 6, metoclopramide (20 mg) was administered 2 hours after the last pretreatment dose of rifampicin. The serial blood samples were collected on predetermined time points (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 18 h) and analyzed using a validated HPLC method for the determination of pharmacokinetic parameters, i.e. Cmax, Tmax, and AUC0-∞ of metoclopramide. The whole study was monitored by an unblinded clinician for the purpose of volunteer\'s health safety.
RESULTS: All the volunteers participated in the study until the end. Twelve healthy Pakistani males having mean age 26.0 (range 20.6-34.1) years and body mass index 25.1 (range 16.2-31.5) kg/m2 were included in this study after taking written informed consent. Rifampicin significantly (P<0.05) decreased the mean Cmax, AUC0-∞ and T1/2 of metoclopramide by 35%, 68%, and 44%, respectively. The laboratory tests did not reveal any significant change in the biochemical, physical, hematological, or urinalytical values before and after metoclopramide treatment. None of the volunteers complained of any discomfort during the study.
CONCLUSIONS: Rifampicin noticeably decreased the concentration of plasma metoclopramide. These results give in vivo confirmation of the CYP3A4 involvement in the metoclopramide metabolism, in addition to CYP2D6. Therefore, metoclopramide pharmacokinetics may be clinically affected by rifampicin and other potent enzyme inducers.

Clopidogrel is an inactive prodrug, it catalyzed into its active form by Cytochrome 450 and Paraoxonase-1(PON-1). polymorphisms of genes encoding these enzymes will affect the efficacy of Clopidogrel. The main objective of our study was to investigate the association of CYP2C19*2, CYP2C19*3 and PON-1Q192R polymorphisms with Clopidogrel resistance and major adverse cardiac events in Jin Hua district in the middle of Zhe Jiang Province in China.
One hundred sixty coronary heart disease patients with percutaneous coronary intervention, who were followed-up for 1 year, were enrolled in our study. These patients were co-administered aspirin 100 mg/d and clopidogrel 75 mg/d following a loading dose of 300 mg. The ADP-induced platelet aggregation rate was measured by Platelet aggregator. Genotypes of CYP2C19*2, CYP2C19*3, PON-1Q192R were determined using Sanger sequencing in all patients. Various clinical data were collected.
The frequencies of CYP2C19*2, CYP2C19*3 and PON-1Q192R homozygous mutant genotypes were significantly lower in non-responders than those in responders. After for all variables, CYP2C19*2, CYP2C19*3 and PON-1Q192R independently increased the risk of clopidogrel resistance with adjusted ORs 46.65(95% CI,1.77-25.04; p = 0.005); 22.74(95% CI, 3.11-166.27; p = 0.002); 5.69 (95% CI,1.06-30.47; p = 0.042). Over a follow-up of 12 months, the incidence of major adverse cardiac events (MACE) in CYP2C19*1/*2, *1/*3, *2/*2, *2/*3 was significantly higher than no mutant genotype (18/40vs.2/63,3/9vs.2/63, 11/6vs.2/63, 7/1vs2/63, respectively). There was no significant correlation between PON-1Q192R mutant allele and MACE.
Our study was first time to report on CYP2C19 and PON-1 polymorphisms in Jin Hua population in the middle of Zhe Jiang province in China. The carriage of CYP2C19*2 or *3 mutant allele significantly reduced the platelet response to clopidogrel and increase the MACE. The carriage of PON-1 mutant allele also significantly reduced the platelet response to clopidogrel, but would not increase the major adverse cardiac events after 1 year follow-up.
ChiCTR, ChiCTR1800018316. Registered 11 September 2018 - prospective registered, http://www.chictr.org.cn/edit.aspx?pid=30927&htm=4.

The spatial distributions of cytochrome P450 (CYP450) and glutathione (GSH) in liver lobules determine the heterogeneous hepatotoxicity of acetaminophen (APAP). Their interplay in conjunction with blood flow is not well understood. In this paper, we integrate a cellular APAP metabolism model with a sinusoidal blood flow to simulate the temporal-spatial patterns of APAP-induced hepatotoxicity. The heterogeneous distribution of CYP450 and GSH is modeled by linearly varying their reaction rates along the portal triad to the central vein axis of a sinusoid. We found that the spatial distribution of GSH, glutathione S-transferases (GSTs), and CYP450 all contributes to the high acetaminophen protein adduct formation at zone 3 of the lobules. The reversed spatial gradients of CYP450 and GSH cause quick depletion of GSH, which is further accelerated by the distribution of GST. The hepatic flow congestion and hyperperfusion however do not seem to play a significant role in the zonal hepatotoxicity. The simulation results may be useful for understanding the APAP-induced hepatotoxicity and associated pharmaceutical treatment.

The hepatic cytochrome P450 (CYP450) enzyme superfamily is one of the most important drug-metabolizing enzyme systems, which is responsible for the metabolism of a large number of clinically relevant medications used in traumatic brain injury (TBI) therapy. Modification of CYP450 expression may have important influences on drug metabolism and lead to untoward effects on those with narrow therapeutic windows. However, the impact of blast-induced TBI (bTBI) on the expression of CYP450 has received little attention. The subfamilies of CYP1A, 2B, 2D, and 3A account for about 85 % of all human drug metabolism of clinical significance. Therefore, in this study, we investigated the expressions of hepatic CYP1A2, CYP2B1, CYP2D1, and CYP3A2 in rats suffering bTBI. Meanwhile, we also measured some important cytokines in serum after injury, and calculated the correlation between these cytokines and the expressions of CYP1A2, CYP2B1, CYP2D1, and CYP3A2. The results showed that bTBI could significantly reduce mRNA expressions of CYP1A2, CYP2D1, and CYP3A2 at the early stage and induce the expressions from 48 h to 1 week after injury. The protein expressions of these CYP450s had all been downregulated from 24 to 48 h post- injury, and then began to elevate at 48 h after bTBI. The cytokines, IL-1β, IL-2, IL-6, and TNF-α, increased significantly in the early phase, and began to reduce at the delayed phase of bTBI. The serum levels of IL-1β, IL-6, and TNF-α but not IL-2 were significantly negative correlated with the mRNA expressions of CYP2B1 and CYP2D1 and the proteins expressions of CYP1A2, CYP2B1, CYP2D1, and CYP3A2. In conclusion, our work has, for the first time, indicated that bTBI has significant impact on the expressions of CYP1A2, CYP2B1, CYP2D1, and CYP3A2, which may be related to the cytokines induced by the injury.

This study aimed to assess cytochrome (CY) P450-2D6*4 polymorphism relationship with semen variables in infertile men. In all, 308 men were included; fertile normozoospermia (N) (n = 77), asthenozoospermia (A) (n = 70), asthenoteratozoospermia (AT) (n = 75) and oligoasthenoteratozoospermia (OAT) (n = 86). They were subjected to history taking, clinical examination, semen analysis, sperm acrosin activity, seminal malondialdehyde (MDA) and CYP450-2D6*4 genotyping. CYP450-2D6*4 wild-type allele was represented in 76.5% of N, 70% of A, 66.7% of AT and 57.7% of OAT men where homozygous gene mutation was present in 5.9% of N, 20% of A, 26.6% of AT and 26.9% of OAT men, respectively. Sperm acrosin activity, sperm concentration, sperm motility, linear sperm velocity and sperm normal forms were significantly higher, and seminal MDA level was significantly lower in men with CYP450-2D6*4 wild-type allele compared with men with homozygous mutation. It is concluded that CYP450-2D6*4 wild-type allele has higher frequency where homozygous-type allele has lower frequency in N men compared with A, AT and OAT men. Sperm acrosin activity index, sperm concentration, sperm motility, linear sperm velocity and sperm normal forms were significantly higher, and seminal MDA level was significantly lower in men with CYP450-2D6*4 wild-type allele compared with men with homozygous mutation.

OBJECTIVE: Statins are safe but have a significant potential for pharmacological interactions. The objective of the study was to evaluate the prevalence of potential interactions throughout the cytochrome P450 isoenzyme 3A4 (CYP3A4) system in a large sample of statin-treated subjects and to determine which factors, from the patient and the physician, were associated with a higher risk of interactions.
METHODS: This is an observational, cross-over, population study that included 7,880 subjects treated with statins. Both data from patients and from the1,681 participating physicians were recorded and analyzed.
RESULTS: Fifty-nine percent of the participants were receiving a statin metabolized by the CYP3A4, and 21.5% of all participants received a drug, different from a statin, metabolized by the CYP3A4. There were no differences in the frequency of utilization of statins metabolized or not by the CYP3A4 in relation to the simultaneous prescription of drugs metabolized by the same pathway (22 vs. 21%, respectively). Globally, 12.9% of all participants were at risk of an interaction. These patients were older, received a higher number of drugs and had more comorbidity. Sixty percent of the physicians mentioned that the possibility of an interaction greatly conditioned their selection of a particular statin. Likewise, 56% of them had software that alerted of possible interactions. These aspects, however, did not influence the number of patients at risk of interactions.
CONCLUSIONS: The proportion of statin-treated patients at risk of interaction is elevated. Physicians do not usually pay attention to this possibility despite having available alert software and therapeutic alternatives.