Optimization of antibiotic therapy in pregnancy – clinical implications

The aim of the antibacterial therapy during pregnancy is to select a proper antibiotic and determine its effective dose, at the same time excluding the risk of potential teratogenic effect. Pregnancy is characterized by many physiological, disease-predisposing changes, particularly of bacterial etiology, that have an influence on different pharmacokinetic of drugs. When determining an effective dose of an antibiotic, one should take into account changes in the pharmacokinetics (PK) of drugs in pregnant women, involving mainly the phase of distribution(increased volume of body fluids, cardiac output, reduced concentration of albumins), metabolism (induction of hepatic enzymes: CYP3A4, CYP2D6, CYP2C9, UGT1A4, UGT2B7, inhibition of CYP1A2, CYP2C19), and excretion (increased glomerular filtration rate). Results of few pharmacokinetic studies on pregnant patients point to the need of increasing the dose or reducing dosage intervals for some antibiotics (e.g. penicillin V, ampicillin, piperacillin, imipenem, clindamycin). The aim of this study was to summarize current knowledge regarding the PK of antibiotics during pregnancy

The Influence of Diabetes Mellitus on Glucuronidation and Sulphation of Paracetamol in Patients with Febrile Neutropenia

Background and Objectives Numerous studies have confirmed the influence of diabetes mellitus on the pharmacokinetics of drugs. Paracetamol (APAP) is an antipyretic that is commonly used in febrile neutropenia (FN) therapy. APAP is chiefly metabolised by glucuronidation and sulphation. This study assessed the influence of diabetes on the pharmacokinetics of paracetamol and its metabolites: glucuronide (APAP-glu) and sulfate (APAP-sulfate) in FN patients. Methods Patients with FN received single intravenous dose 1000 mg of APAP. The FN patients were allocated to one of two groups: diabetics (DG, n = 7) or non-diabetics (NDG, n = 11). The plasma concentrations of paracetamol and its metabolites were measured with the validated high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Results Pharmacokinetic parameters (mean [SD]) of APAP in the DG and NDG groups were as follows: Cmax (maximum comcentration) = 21.50 [11.23] vs. 23.42 [9.79] mg/L, AUC 0–t (area under the concentration–time curve) = 44.23 [17.93] vs. 41.43 [14.57] mg·h/L, t1/2kel (elimination half-life) = 2.28 [0.80] vs. 2.11 [0.80] h. In both groups the exposure to APAP was comparable. The study did not reveal differences between the two groups in the pharmacokinetics of APAP-glu and APAP-sulfate. The Cmax and AUC 0–t ratio between the metabolites and APAP were similar. Conclusions No differences in the pharmacokinetics of APAP, APAP-glu and APAP-sulfate in patients with FN indicates that diabetes does not influence glucuronidation and sulfatation of paracetamol

The concomitant use of lapatinib and paracetamol - the risk of interaction

Lapatinib is a tyrosine kinase inhibitor used for the treatment of breast cancer. Paracetamol is an analgesic commonly applied to patients with mild or moderate pain and fever. Cancer patients are polymedicated, which involves high risk of drug interactions during therapy. The aimof the study was to assess the interaction between lapatinib and paracetamol in rats. The rats were divided into three groups of eight animals in each. One group received lapatinib + paracetamol (IL+PA), another group received lapatinib (IIL), whereas the last group received paracetamol (IIIPA). A single dose of lapatinib (100 mg/kg b.w.) and paracetamol (100 mg/ kg b.w.) was administered orally. Plasma concentrations of lapatinib, paracetamol and its metabolites – glucuronide and sulphate, were measured with the validated HPLC-MS/MS method and HPLC-UV method, respectively. The pharmacokinetic parameters of both drugs were calculated using non-compartmental methods. The co-administration of lapatinib and paracetamol increased the area under the plasma concentration-time curve (AUC) and the maximum concentration (Cmax) of lapatinib by 239.6% (p = 0.0030) and 184% (p = 0.0011), respectively. Lapatinib decreased the paracetamol AUC0-∞ by 48.8% and Cmax by 55.7%. In the IL+PA group the Cmax of paracetamol glucuronide was reduced, whereas the Cmax of paracetamol sulphate was higher than in the IIIPA group. Paracetamol significantly affected the enhanced plasma exposure of lapatinib. Additionally, lapatinib reduced the concentrations of paracetamol. The co-administration of lapatinib decreased the paracetamol glucuronidation but increased the sulphation. The findings of this study may be of clinical relevance to patients requiring analgesic therapy

The Effects of Bariatric Surgery and Gastrectomy on the Absorption of Drugs, Vitamins, and Mineral Elements

Bariatric surgery, which is an effective treatment for obesity, and gastrectomy, which is the primary treatment method for gastric cancer, alter the anatomy and physiology of the digestive system. Weight loss and changes in the gastrointestinal tract may affect the pharmacokinetic parameters of oral medications. Both bariatric and cancer patients use drugs chronically or temporarily. It is important to know how surgery affects their pharmacokinetics to ensure an effective and safe therapy. The Cochrane, PubMed, and Scopus databases were searched independently by two authors. The search strategy included controlled vocabulary and keywords. Studies show that bariatric surgery and gastrectomy most often reduce the time to maximum plasma concentration (tmax) and decrease the maximum plasma concentration (Cmax) in comparison with the values of these parameters measured in healthy volunteers. Vitamin and mineral deficiencies are also observed. The effect depends on the type of surgery and the properties of the drug. It is recommended to use the drugs that have been tested on these groups of patients as it is possible to monitor them

Analgesic efficacy and safety of tapentadol in comparison with oxycodone in patients after open abdominal hysterectomy.

Tapentadol is the newest opioid with dual mechanism of action, that gives the potential to spare some opioid-induced adverse events. Studies involving this drug in acute pain are not numerous. The aim of this study was to compare the efficacy and tolerance of tapentadol and oxycodone in patients after abdominal hysterectomy. Patients were randomly allocated into two groups receiving: I. tapentadol (50 mg) and II. oxycodone (10 mg), every 12 hours postoperatively. The Numerical Rating Scores (NRS), vital signs, main adverse events (postoperative nausea and vomiting, sedation) and other side effects would be recorded until discharge. Total opioid consumption, the patients’ satisfaction, adjuvants consumption, and length of hospital stay were also assessed Mean NRS scores for tapentadol and oxycodone after 24, 48 and 72 hours were: 3.43 (±1.29) vs 3.59 (±1.37), 2.87 (±1.07) vs 3.24 (±1.21), 2.80 (±1.05) vs 3.19 (±1.24), respectively. In the tapentadol group, superior pain control (p0.05). Mucosal dryness affected over >90% patients in both groups. The incidence of postoperative nausea was 39.5% (tapentadol) and 27% (oxycodone) on the first day. The incidence of drowsiness was 42.1% (tapentadol) and 37.8% (oxycodone). Other adverse events’ level, satisfaction with treatment, length of stay after surgery, effect on vital signs were comparable

Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats

A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic— morphine—can be found in the treatment of cancer patients. Since both are substrates of Pglycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug–drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curves (AUC0–t, and AUC0–¥) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0–t of its active metabolite—sorafenib N-oxide—was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0–t, and AUC0–¥ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects

In vivo assessment of potential for UGT-inhibition-based drug-drug interaction between sorafenib and tapentadol

Sorafenib (SR) is one of the most potent UGT (1A1, 1A9) inhibitors (in in vitro tests). The inhibition of UGT1A1 may cause hyperbilirubinaemia, whereas the inhibition of UGT1A9 and 1A1 may result in drug-drug interactions (DDIs). Tapentadol (TAP) is a synthetic μ-opioid agonist and is used to treat moderate to severe acute pain. Tapentadol is highly glucuronidated by the UGT1A9 and UGT2B7 isoenzymes. The aim of the study was to assess the DDI between SR and TAP. Wistar rats were divided into three groups, with eight animals in each. The rats were orally treated with SR (100 mg/kg) or TAP (4.64 mg/kg) or in combination with 100 mg/kg SOR and 4.64 TAP mg/kg. The concentrations of SR and sorafenib N-oxide, TAP and tapentadol glucuronide were respectively measured by means of high-performance liquid chromatography (HPLC) with ultraviolet detection and by means of ultra-performance liquid chromatography-tandem mass spectrometry. The co-administration of TAP with SR caused TAP maximum plasma concentration (Cmax) to increase 5.3-fold whereas its area under the plasma concentration-time curve (AUC0-∞) increased 1.5-fold. The tapentadol glucuronide Cmax increased 5.3-fold and whereas its AUC0-∞ increased 2.0-fold. The tapentadol glucuronide/TAP AUC0–∞ ratio increased 1.4-fold (p = 0.0118). TAP also increased SR Cmax 1.9-fold, whereas its AUC0-∞ increased 1.3-fold. The sorafenib N-oxide Cmax increased 1.9-fold whereas its AUC0-∞ increased 1.3-fold. The sorafenib N-oxide/SR AUC0–t ratio increased 1.4-fold (p = 0.0127). The results show that the co-administration of sorafenib and tapentadol increases the exposure to both drugs and changes their metabolism. In consequence, the pharmacological effect may be intensified, but the toxicity may increases, too.This article is published as Karbownik, Agnieszka, Miłosz Miedziaszczyk, Tomasz Grabowski, Joanna Stanisławiak-Rudowicz, Radosław Jaźwiec, Anna Wolc, Edmund Grześkowiak, and Edyta Szałek. "In vivo assessment of potential for UGT-inhibition-based drug-drug interaction between sorafenib and tapentadol." Biomedicine & Pharmacotherapy 130 (2020): 110530. doi: 10.1016/j.biopha.2020.110530.</p

The Influence of Diabetes Mellitus on Glucuronidation and Sulphation of Paracetamol in Patients with Febrile Neutropenia

Background and Objectives Numerous studies have confirmed the influence of diabetes mellitus on the pharmacokinetics of drugs. Paracetamol (APAP) is an antipyretic that is commonly used in febrile neutropenia (FN) therapy. APAP is chiefly metabolised by glucuronidation and sulphation. This study assessed the influence of diabetes on the pharmacokinetics of paracetamol and its metabolites: glucuronide (APAP-glu) and sulfate (APAP-sulfate) in FN patients. Methods Patients with FN received single intravenous dose 1000 mg of APAP. The FN patients were allocated to one of two groups: diabetics (DG, n = 7) or non-diabetics (NDG, n = 11). The plasma concentrations of paracetamol and its metabolites were measured with the validated high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Results Pharmacokinetic parameters (mean [SD]) of APAP in the DG and NDG groups were as follows: Cmax (maximum comcentration) = 21.50 [11.23] vs. 23.42 [9.79] mg/L, AUC 0–t (area under the concentration–time curve) = 44.23 [17.93] vs. 41.43 [14.57] mg·h/L, t1/2kel (elimination half-life) = 2.28 [0.80] vs. 2.11 [0.80] h. In both groups the exposure to APAP was comparable. The study did not reveal differences between the two groups in the pharmacokinetics of APAP-glu and APAP-sulfate. The Cmax and AUC 0–t ratio between the metabolites and APAP were similar. Conclusions No differences in the pharmacokinetics of APAP, APAP-glu and APAP-sulfate in patients with FN indicates that diabetes does not influence glucuronidation and sulfatation of paracetamol.This article is published as Stachowiak, A., Szałek, E., Karbownik, A. et al. The Influence of Diabetes Mellitus on Glucuronidation and Sulphation of Paracetamol in Patients with Febrile Neutropenia. Eur J Drug Metab Pharmacokinet 44, 289–294 (2019). doi: 10.1007/s13318-018-0508-4.</p