Applications for pharmacogenomics in pharmacy practice: A scoping review.

BACKGROUND: Pharmacogenomics (PGx) can provide valuable pharmacokinetic and pharmacodynamic information for the pharmacist's assessment of drug therapy, especially within medication therapy management (MTM) services. However, no review has comprehensively mapped the pharmacists' use of PGx in practice-based research. Doing so would allow future researchers, practitioners, and policy-makers to identify the ideal populations and settings for PGx implementation within the pharmacy. OBJECTIVE: The purpose of this review is to identify the evidence to date of PGx use in pharmacy practice. METHODS: A scoping review was conducted to find all studied non-oncologic pharmacy practices incorporating PGx testing. Search terms were applied to 5 databases and relevant journals. Characteristics of patients, pharmacy settings, genetic tests, and outcomes were summarized to determine models most likely to benefit patients. RESULTS: The search identified 43 studies on the use of PGx by pharmacists published between 2007 and 2020. CYP2C19 testing with antiplatelets was the most studied model, found in both community and institutional settings. It also was the most actionable test: approximately 30% of patients have polymorphisms indicating a need for alternative antiplatelets, and identifying these patients can reduce morbidity and mortality by more than 50%. As technology shifts, broader studies using multi-gene panel tests within MTM demonstrate an approximate 50% decrease in emergency visits and hospitalizations in elderly polypharmacy patients. Clinical benefit or drug-gene interactions are also found in other cardiovascular, psychiatric, analgesic, and gastrointestinal indications. No evaluations of actual costs or of pharmacist prescribing within pharmacy-based PGx have been performed. Facilitators towards successful PGx implementation included pharmacist education, collaboration with other healthcare providers, and the use of clinical decision software. CONCLUSIONS: Pharmacogenomic testing has demonstrated feasibility and improved medication outcomes in pharmacy practice, including in the community pharmacy. Further PGx research should be directed towards pharmacist prescribing, pharmacist education, and pharmacoeconomics.

Pharmacokinetic interaction between linagliptin and tadalafil in healthy Egyptian males using a novel LC-MS method.

Aim: Assessment of pharmacokinetic interaction between linagliptin (LNG) and tadalafil (TDL) in healthy males. Methods: First, a novel LC-MS method was developed; second, a Phase IV, open-label, cross-over study was performed. Volunteers took single 20-mg TDL dose on day 1 followed by wash out period of 2 weeks then multiple oral dosing of 5-mg/day LNG for 13 days. On day 13, volunteers were co-administered 20-mg TDL. Results: LNG and TDL single doses did not affect QTc interval. Smoking did not alter pharmacokinetics/pharmacodynamics of LNG and TDL. Co-administration of LNG with TDL resulted in TDL longer time to reach maximum plasma concentration (Tmax), decreased oral clearance (Cl/F) and oral volume of distribution (Vd/F), increased its maximum plasma concentration (Cmax), area under concentration-time curve (AUC), muscle pain and QTc prolongation. Conclusion: LNG and TDL co-administration warrants monitoring and/or TDL dose adjustment.

Novel cremochylomicrons for improved oral bioavailability of the antineoplastic phytomedicine berberine chloride: Optimization and pharmacokinetics.

Berberine chloride (BER) is an antineoplastic phytomedicine that combat non-Hodgkin lymphoma. BER suffers from low oral bioavailability due to p-glycoprotein efflux and first-pass metabolism. Lymphatic drug targeting recently gained a profound attention due to circumventing hepatic first-pass metabolism and targeting lymph diseases. Therefore, novel BER-loaded cremochylomicrons were elaborated to mitigate BER drawbacks and enhance its lymphatic targeting and bioavailability. Optimized cremochylomicron was prepared with 2.5%w/v Cremophor El and 12.5% w/w berberine content. Promising in vitro characteristics (particle size = 175.6 nm and entrapment efficiency = 95.5%) were obtained. Lyophilized system showed high colloidal stability over 6 months. In addition in vivo pharmacokinetics study demonstrated significant enhancement (>2fold) in the rate and extent of absorption in cremochylomicron over free BER. Moreover, cremochylomicrons demonstrated in significant increase in mean residence time and volume of distribution with decreased intestinal drug clearance as a result of efflux inhibition. In another avenue, a significant reduction in BER absorption (43%) in presence of cycloheximide inhibitor was obtained confirming the lymphatic targeting ability of cremochylomicrons. In conclusion, berberine-loaded cremochylomicron could be considered as a promising nanoplatform for targeting lymphatic system and improving BER oral bioavailability with lower dose and side effects.

Hyperlipidemia Alters the Pharmacokinetics of Posaconazole and Vincristine Upon Co-Administration in Rats.

OBJECTIVES: Co-administration of posaconazole (PSZ) and vincristine (VCR) in the treatment of patients with acute lymphoblastic leukemia increases the neurotoxicity of VCR. Our aim is to study the effect of increased lipoprotein levels on the pharmacokinetics of PSZ and VCR upon co-administration in rats. METHODS: Rats were assigned to three groups, normolipidemic (NL), intermediate hyperlipidemic (IHL), and extreme hyperlipidemic (HL) groups. All rats were administered PSZ orally followed by VCR intravenously 4 h later. For the pharmacokinetic study, serial plasma samples were collected over 96 h and for tissue distribution study; plasma, lung, and liver tissues were collected over 48 h post oral dosing. RESULTS: Posaconazole showed higher plasma concentrations than VCR at all time points. Co-administration of VCR with PSZ reduced PSZ weight normalized oral clearance, increased PSZ area under the plasma concentration-time curve (AUC) from time zero to infinity, showed higher PSZ liver concentrations, and increased VCR volume of distribution of the central compartment. Upon increasing the lipoprotein levels, PSZ showed higher plasma availability and delayed tissue distribution, whereas VCR had shown a significant decrease in PSZ AUC0-24h, AUC0-tlast, and AUCo-inf (NL = IHL > HL) and a significant increase in the volume of distribution (NL = IHL < HL). Vincristine has shown higher tissue uptake and concentrations. CONCLUSION: Monitoring cholesterol and triglyceride levels in patients with acute lymphoblastic leukemia is advisable to decrease VCR neurological side effect incidences and delay the activity of both PSZ and VCR.

The effect of increased lipoproteins levels on the disposition of vincristine in rat.

BACKGROUND: Vincristine (VCR), an antineoplastic agent, is a key component in the treatment of acute lymphoblastic leukemia, lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor diseases. Recently, high incidence of hyperlipidemia was reported to be associated with allogenic hematopoietic stem cell transplantation and VCR/L-asparaginase therapy. The aim of this study is to test the effects of incremental increase in lipoproteins levels on vincristine disposition in rat. METHOD: To study VCR pharmacokinetics and protein binding, rats (n = 25) were assigned to three groups, normal lipidemic (NL), intermediate (IHL) and extreme hyperlipidemic (HL). Hyperlipidemia was induced by ip injection of (1 g/Kg) poloxamer 407 in rats. Serial blood samples were collected using the pre-inserted jugular vein cannula for 72 h post VCR (0.15 mg/Kg) i.v. dose. VCR unbound fractions in NL, IHL and HL plasma were determined using ultrafiltration kits. RESULTS: VCR demonstrated a rapid distribution phase (6-8 h) followed by a slower elimination phase with a mean elimination t½ of ~ 14 h. VCR exhibited moderate binding to plasma proteins ~ 83 %. It showed a relatively small Vc (~0.17 L/Kg) and a larger Vß (1.53 L/Kg) indicating good tissue distribution. As the lipoproteins levels were increased, no significant changes were noted in VCR unbound fraction, plasma concentration, or volume of distribution indicating low affinity to lipoprotein binding. Induced HL also did not affect VCR elimination where similar VCR AUC0-∞, Cl and elimination phase t½ were reported along the different lipemic groups. CONCLUSION: Incremental increase in lipoprotein levels resulted in no significant effect on VCR disposition as such ALL malignant lymphoma and allogenic hematopoietic stem cell transplantation patients need not to worry about HL-VCR interaction. Whether, HL can potentiate another drug-drug or drug-disease interaction involving VCR warrants further studying and monitoring to ensure therapeutic safety and efficiency.

HPLC Methods for Quantitation of Exemestane-Luteolin and Exemestane-Resveratrol Mixtures in Nanoformulations.

Two HPLC-DAD assays for the simultaneous quantitation of exemestane (EXE) and resveratrol (RES)-Mix 1-and EXE and luteolin (LUT)-Mix 2-in novel breast cancer therapy nanoformulations were developed. Calibration curves 15-30 µg/mL and samples were injected through an Inertsil ODS-3 (250 × 4.6 mm, 5 µm) column. The gradient elution for Mix 1 was methanol : 0.05% (v/v) acetic acid in water (60 : 40 to 80 : 20, linear over 2 min), and for Mix 2, it was methanol : water (60 : 40 for 4 min, then ramped linearly to 90 : 10, over 12 min) pumped at 1.5 mL/min for 4 min, then 1 mL/min till the end of run. EXE, RES, LUT and flutamide (internal standard (IS)) were measured at 246, 307, 350 and 300 nm, respectively. For Mix 1, RES, EXE and IS eluted at 3.5, 6.8 and 7.4 min, respectively, while for Mix 2, LUT, EXE and IS eluted at 7.5, 11.4 and 12.7 min, respectively. The mean r(2) for the standard curves was ≥0.99, and percentage coefficient of variation and % error of the mean were <2. Both assays successfully quantitated Mix 1 and Mix 2 in their nanoformulations. The two developed assays were sensitive and selective for the analysis of EXE-LUT and EXE-RES mixtures in nanoformulations according to International Conference on Harmonization guidelines.

Ketoconazole Stereoisomers Differentially Induce Cytochrome P450 1A1 Between Human Hepatoma HepG2 and Mouse Hepatoma Hepa1c1c7 Cells.

Ketoconazole (KTZ) has 2 chiral centers with the therapeutically active form being a racemic mixture of 2 cis-enantiomers, namely, (2R,4S)-(+)-KTZ and (2S,4R)-(-)-KTZ. The aims of the present study were to examine the effects of (+)-KTZ, (-)-KTZ, and (±)-KTZ on aryl hydrocarbon receptor activation and subsequently CYP1A1 induction in both human HepG2 and murine Hepa1c1c7 hepatoma cells, and to further test their inhibitory effect using recombinant human and mouse CYP1A1 enzymes. Our results demonstrated that (+)-KTZ induced human CYP1A1 more than (-)-KTZ, whereas on the other hand (-)-KTZ induced murine Cyp1a1 more than (+)-KTZ at the mRNA, and activity levels. Human CYP1A1 showed higher affinity to 7ER compared with murine Cyp1a1 (Km values 13.29 nM for human vs. 168.1 nM for murine). The intrinsic clearance values for human and murine CYP1A1 were 194.1 and 87.6 µL/pmol P450/min, respectively, whereas, Vmax values were 2.58 and 14.73 pmol/pmol P450/min, respectively. (+)-KTZ and (-)-KTZ directly inhibited CYP1A1 activity by noncompetitive mechanism. The affinity of (-)-KTZ to interact with human CYP1A1 and murine Cyp1a1 was significantly different from (+)-KTZ, as the Ki values for human CYP1A1 and murine Cyp1a1 were 199.4 and 413.7 nM, respectively, for (+)-KTZ, and 269.3 and 230.8 nM, respectively, for (-)-KTZ.

Effect of rat serum lipoproteins on mRNA levels and amiodarone metabolism by cultured primary rat hepatocytes.

Hyperlipidemia can significantly increase amiodarone (AM) in vivo liver uptake and decrease its velocity of microsomal metabolism. Here, hepatocytes isolated from normolipidemic (NL) and hyperlipidemic rats were incubated with AM in the presence or absence of diluted NL or hyperlipidemic serum. The serum was added either as preincubation before drug, or concurrently with drug; incubations without rat serum were used as controls. The hepatocyte levels of mRNA for several proteins and enzymes were also measured. Disappearance of AM was seen up to 72 h. There was little difference between hepatocytes from NL or hyperlipidemic animals in intrinsic clearance (CL(int) ) of AM. The effect of hyperlipidemic rat serum, either before or with AM, was profound, causing a significant reduction in the CL(int) . Reductions were seen in mRNA for cytochrome P450 1A1, 3A2, and 2D1, some transporters, and low-density lipoprotein receptors after exposure of hepatocytes to lipoprotein-rich sera. In conclusion, exposure of isolated hepatocytes to hyperlipidemic serum caused decreases in AM CL(int) and lower mRNA levels for some proteins involved in the uptake and metabolism of AM. When coincubated with serum, an additional effect of increased binding to lipoproteins seemed to further contribute to a reduced CL of AM.

Posaconazole-vincristine coadministration triggers seizure in a young female adult: a case report.

Coadministration of azoles and vincristine has been shown to increase vincristine neurotoxic effects due to the inhibition of cytochrome P450 (CYP) isoform 3A4, for which vincristine is a substrate. Despite the absence of any casual relationship between seizure and coadministration of azoles, few case reports of vincristine-induced seizure have been documented after coadministration of fluconazole or posaconazole in children. In this paper we are reporting the first young female adult who experienced generalized seizure after coadministration of posaconazole and vincristine. The 19-year-old female was diagnosed with acute lymphoblastic leukemia. She started induction phase of Berlin Frankfurt Muenster protocol along with posaconazole 200 mg three times daily as prophylactic antifungal therapy. Five days after the third vincristine dose, she developed generalized seizure accompanied by high blood pressure and SIADH. Her neurological exam/CT scan did not show any abnormality. In conclusion, this study reports a novel finding in the sense that all previous case reports pertaining to posaconazole-vincristine-induced seizure in literature involved children. Physicians should be made aware of this rare possible outcome to closely monitor their patients and take appropriate measures to prevent such possible adverse effect.