Showing papers on "Pharmacokinetics published in 2003"

Effect of pegylation on pharmaceuticals

Abstract: Protein and peptide drugs hold great promise as therapeutic agents. However, many are degraded by proteolytic enzymes, can be rapidly cleared by the kidneys, generate neutralizing antibodies and have a short circulating half-life. Pegylation, the process by which polyethylene glycol chains are attached to protein and peptide drugs, can overcome these and other shortcomings. By increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes, pegylation improves pharmacokinetics. This article will review how PEGylation can result in drugs that are often more effective and safer, and which show improved patient convenience and compliance.

Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies.

Abstract: Pegylated liposomal doxorubicin (doxorubicin HCl liposome injection; Doxil® or Caelyx®) is a liposomal formulation of doxorubicin, reducing uptake by the reticulo-endothelial system due to the attachment of polyethylene glycol polymers to a lipid anchor and stably retaining drug as a result of liposomal entrapment via an ammonium sulfate chemical gradient. These features result in a pharmacokinetic profile characterised by an extended circulation time and a reduced volume of distribution, thereby promoting tumour uptake. Preclinical studies demonstrated one- or two-phase plasma concentration-time profiles. Most of the drug is cleared with an elimination half-life of 20–30 hours. The volume of distribution is close to the blood volume, and the area under the concentration-time curve (AUC) is increased at least 60-fold compared with free doxorubicin. Studies of tissue distribution indicated preferential accumulation into various implanted tumours and human tumour xenografts, with an enhancement of drug concentrations in the tumour when compared with free drug. Clinical studies of pegylated liposomal doxorubicin in humans have included patients with AIDS-related Kaposi’s sarcoma (ARKS) and with a variety of solid tumours, including ovarian, breast and prostate carcinomas. The pharmacokinetic profile in humans at doses between 10 and 80 mg/m2 is similar to that in animals, with one or two distribution phases: an initial phase with a half-life of 1–3 hours and a second phase with a half-life of 30–90 hours. The AUC after a dose of 50 mg/m2 is approximately 300-fold greater than that with free drug. Clearance and volume of distribution are drastically reduced (at least 250-fold and 60-fold, respectively). Preliminary observations indicate that utilising the distinct pharmacokinetic parameters of pegylated liposomal doxorubicin in dose scheduling is an attractive possibility. In agreement with the preclinical findings, the ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients. There is evidence of selective tumour uptake in malignant effusions, ARKS skin lesions and a variety of solid tumours. The toxicity profile of pegylated liposomal doxorubicin is characterised by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression, decreased cardiotoxicity compared with free doxorubicin and minimal alopecia. The mucocutaneous toxicities are dose-limiting per injection; however, the reduced cardiotoxicity allows a larger cumulative dose than that acceptable for free doxorubicin. Thus, pegylated liposomal doxorubicin represents a new class of chemotherapy delivery system that may significantly improve the therapeutic index of doxorubicin.

Role of P-glycoprotein in pharmacokinetics: clinical implications.

Abstract: P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition. Because of its localisation, P-glycoprotein appears to have a greater impact on limiting cellular uptake of drugs from blood circulation into brain and from intestinal lumen into epithelial cells than on enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. However, the relative contribution of intestinal P-glycoprotein to overall drug absorption is unlikely to be quantitatively important unless a very small oral dose is given, or the dissolution and diffusion rates of the drug are very slow. This is because P-glycoprotein transport activity becomes saturated by high concentrations of drug in the intestinal lumen. Because of its importance in pharmacokinetics, P-glycoprotein transport screening has been incorporated into the drug discovery process, aided by the availability of transgenic mdr knockout mice and in vitro cell systems. When applying in vitro and in vivo screening models to study P-glycoprotein function, there are two fundamental questions: (i) can in vitro data be accurately extrapolated to the in vivo situation; and (ii) can animal data be directly scaled up to humans? Current information from our laboratory suggests that in vivo P-glycoprotein activity for a given drug can be extrapolated reasonably well from in vitro data. On the other hand, there are significant species differences in P-glycoprotein transport activity between humans and animals, and the species differences appear to be substrate-dependent. Inhibition and induction of P-glycoprotein have been reported as the causes of drug-drug interactions. The potential risk of P-glycoprotein-mediated drug interactions may be greatly underestimated if only plasma concentration is monitored. From animal studies, it is clear that P-glycoprotein inhibition always has a much greater impact on tissue distribution, particularly with regard to the brain, than on plasma concentrations. Therefore, the potential risk of P-glycoprotein-mediated drug interactions should be assessed carefully. Because of overlapping substrate specificity between cytochrome P450 (CYP) 3A4 and P-glycoprotein, and because of similarities in P-glycoprotein and CYP3A4 inhibitors and inducers, many drug interactions involve both P-glycoprotein and CYP3A4. Unless the relative contribution of P-glycoprotein and CYP3A4 to drug interactions can be quantitatively estimated, care should be taken when exploring the underlying mechanism of such interactions.

Pharmacokinetic interactions with rifampicin : clinical relevance.

Abstract: The antituberculosis drug rifampicin (rifampin) induces a number of drug-metabolising enzymes, having the greatest effects on the expression of cytochrome P450 (CYP) 3A4 in the liver and in the small intestine. In addition, rifampicin induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein. Full induction of drug-metabolising enzymes is reached in about 1 week after starting rifampicin treatment and the induction dissipates in roughly 2 weeks after discontinuing rifampicin. Rifampicin has its greatest effects on the pharmacokinetics of orally administered drugs that are metabolised by CYP3A4 and/or are transported by P-glycoprotein. Thus, for example, oral midazolam, triazolam, simvastatin, verapamil and most dihydropyridine calcium channel antagonists are ineffective during rifampicin treatment. The plasma concentrations of several anti-infectives, such as the antimycotics itraconazole and ketoconazole and the HIV protease inhibitors indinavir, nelfinavir and saquinavir, are also greatly reduced by rifampicin. The use of rifampicin with these HIV protease inhibitors is contraindicated to avoid treatment failures. Rifampicin can cause acute transplant rejection in patients treated with immunosuppressive drugs, such as cyclosporin. In addition, rifampicin reduces the plasma concentrations of methadone, leading to symptoms of opioid withdrawal in most patients. Rifampicin also induces CYP2C-mediated metabolism and thus reduces the plasma concentrations of, for example, the CYP2C9 substrate (S)-warfarin and the sulfonylurea antidiabetic drugs. In addition, rifampicin can reduce the plasma concentrations of drugs that are not metabolised (e.g. digoxin) by inducing drug transporters such as P-glycoprotein. Thus, the effects of rifampicin on drug metabolism and transport are broad and of established clinical significance. Potential drug interactions should be considered whenever beginning or discontinuing rifampicin treatment. It is particularly important to remember that the concentrations of many of the other drugs used by the patient will increase when rifampicin is discontinued as the induction starts to wear off.

Pharmacological effects of formulation vehicles : implications for cancer chemotherapy.

Abstract: ol triricinoleate 35) and polysorbate 80 (Tween 80; polyoxyethylene-sorbitan-20-monooleate) are widely used as drug formulation vehicles, including for the taxane anticancer agents paclitaxel and docetaxel. A wealth of recent experimental data has indicated that both solubilisers are biologically and pharmacologically active compounds, and their use as drug formulation vehicles has been implicated in clinically important adverse effects, including acute hypersensitivity reactions and peripheral neuropathy. CrEL and Tween 80 have also been demonstrated to influence the disposition of solubilised drugs that are administered intravenously. The overall resulting effect is a highly increased systemic drug exposure and a simultaneously decreased clearance, leading to alteration in the pharmacodynamic characteristics of the solubilised drug. Kinetic experiments revealed that this effect is primarily caused by reduced cellular uptake of the drug from large spherical micellar-like structures with a highly hydrophobic interior, which act as the principal carrier of circulating drug. Within the central blood compartment, this results in a profound

Clinical pharmacokinetics of atorvastatin.

Abstract: Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease. Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. The clinical dosage range for atorvastatin is 10–80 mg/day, and it is given in the acid form. Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration. However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98%. Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of atorvastatin acid. In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin. Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3. Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated. An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs. Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.

AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function.

Abstract: Testosterone replacement in hypogonadal men improves body composition, mood, and sexual functioning. In this 90-d study, we compared the pharmacokinetics and treatment effectiveness of a topical testosterone gel (AA2500) at two concentrations, 50 mg/d and 100 mg/d, to a testosterone patch and placebo gel in 406 hypogonadal men. Pharmacokinetic profiles were obtained, body composition was measured, and mood and sexual function were monitored. AA2500 treatments resulted in dose-dependent improvements in all pharmacokinetic parameters, compared with testosterone patch and placebo. Mean average concentrations at d 90 T were 13.8, 17.1, 11.9, and 7.3 nmol/liter for 50 mg/d AA2500, 100 mg/d AA2500, testosterone patch, and placebo, respectively. At d 90, the 100 mg/d AA2500 treatment improved lean body mass by 1.7 kg and percentage of body fat by 1.2% to a significantly greater degree than either control treatment. Significant improvements in spontaneous erections, sexual desire, and sexual motivation were also evidenced with the 100 mg/d AA2500 dose in comparison with placebo. Testosterone gel was well tolerated; however, the testosterone patch resulted in a high rate of application site reactions. Overall, AA2500 is an effective, well tolerated treatment for hypogonadism.

Daptomycin Pharmacokinetics and Safety following Administration of Escalating Doses Once Daily to Healthy Subjects

Abstract: The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight (∼20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life (∼9 h), volume of distribution (∼0.1 liters/kg), systemic clearance (∼8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h (∼54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.

Poly (dl-lactide-co-glycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis

Abstract: Objectives: To improve the bioavailability of antitubercular drugs (ATDs) as well as to assess the feasibility of administering ATDs via the respiratory route, this study reports the formulation of three frontline ATDs, i.e. rifampicin, isoniazid and pyrazinamide encapsulated in poly (DL-lactide-co-glycolide) nanoparticles suit- able for nebulization. Methods: Drug-loaded nanoparticles were prepared by the multiple emulsion technique, vacuum-dried and nebulized to guinea pigs. The formulation was evaluated with respect to the pharmacokinetics of each drug and its chemotherapeutic potential in Mycobacterium tuberculosis infected guinea pigs. Results: The aerosolized particles exhibited a mass median aerodynamic diameter of 1.88 ± 0.11 µm, favour- able for bronchoalveolar lung delivery. A single nebulization to guinea pigs resulted in sustained thera- peutic drug levels in the plasma for 6-8 days and in the lungs for up to 11 days. The elimination half-life and mean residence time of the drugs were significantly prolonged compared to when the parent drugs were administered orally, resulting in an enhanced relative bioavailability (compared to oral administration) for encapsulated drugs (12.7-, 32.8- and 14.7-fold for rifampicin, isoniazid and pyrazinamide, respectively). The absolute bioavailability (compared to intravenous (iv) administration) was also increased by 6.5-, 19.1- and 13.4-fold for rifampicin, isoniazid and pyrazinamide, respectively. On nebulization of nanoparticles contain- ing drugs to M. tuberculosis infected guinea pigs at every 10th day, no tubercle bacilli could be detected in the lung after five doses of treatment whereas 46 daily doses of orally administered drug were required to obtain an equivalent therapeutic benefit.

Pharmacokinetics-Pharmacodynamics of Rifampin in an Aerosol Infection Model of Tuberculosis

Abstract: Limited information exists on the pharmacokinetic (PK)-pharmacodynamic (PD) relationships of drugs against Mycobacterium tuberculosis. Our aim was to identify the PK-PD parameter that best describes the efficacy of rifampin on the basis of in vitro and PK properties. Consistent with 83.8% protein binding by equilibrium dialysis, the rifampin MIC for M. tuberculosis strain H37Rv rose from 0.1 in a serum-free system to 1.0 mg/ml when it was tested in the presence of 50% serum. In time-kill studies, rifampin exhibited area under the concentration-time curve (AUC)-dependent killing in vitro, with maximal killing seen on all days and with the potency increasing steadily over a 9-day exposure period. MIC and time-kill studies performed with intracellular organisms in a macrophage monolayer model yielded similar results. By use of a murine aerosol infection model with dose ranging and dose fractionation over 6 days, the PD parameter that best correlated with a reduction in bacterial counts was found to be AUC/MIC (r(2) = 0.95), whereas the maximum concentration in serum/MIC (r(2) = 0.86) and the time that the concentration remained above the MIC (r(2) = 0.44) showed lesser degrees of correlation.

Phase I Clinical Trial of Weekly Combretastatin A4 Phosphate: Clinical and Pharmacokinetic Results

Abstract: Purpose: A phase I trial was performed with combretastatin A4 phosphate (CA4P), a novel tubulin-binding agent that has been shown to rapidly reduce blood flow in animal tumors. Patients and Methods: The drug was delivered by a 10-minute weekly infusion for 3 weeks followed by a week gap, with intrapatient dose escalation. Dose escalation was accomplished by doubling until grade 2 toxicity was seen. The starting dose was 5 mg/m2. Results: Thirty-four patients received 167 infusions. CA4P was rapidly converted to the active combretastatin A4 (CA4), which was further metabolized to the glucuronide. CA4 area under the curve (AUC) increased from 0.169 at 5 mg/m2 to 3.29 μmol • h/L at 114 mg/m2. The mean CA4 AUC in eight patients at 68 mg/m2 was 2.33 μmol • h/L compared with 5.8 μmol • h/L at 25 mg/kg (the lowest effective dose) in the mouse. The only toxicity that possibly was related to the drug dose up to 40 mg/m2 was tumor pain. Dose-limiting toxicity was reversible ataxia at 114 mg/m2, vasovagal syncope an...

Bioavailability, Disposition, and Dose-Response Effects of Soy Isoflavones When Consumed by Healthy Women at Physiologically Typical Dietary Intakes

Abstract: The pharmacokinetics of isoflavones in 10 healthy women were determined from serum appearance/disappearance concentration profiles and urinary excretions after single-bolus ingestion of 10, 20 or 40 g of soy nuts delivering increasing amounts of the conjugated forms of daidzein (6.6, 13.2 and 26.4 mg) and genistein (9.8, 19.6 and 39.2 mg). Peak serum daidzein and genistein concentrations were attained after 4-8 h, and elimination half-lives were 8.0 and 10.1 h, respectively. There were no differences in the pharmacokinetics of daidzein and genistein between pre- and postmenopausal women, indicating absorption and disposition of isoflavones to be independent of age or menopausal status. A curvilinear relationship was observed between the bioavailability of daidzein and genistein, apparent from the area under the curve to infinity (AUC(inf)) of the serum concentration-time profiles and the amount of isoflavones ingested. The mean fraction of the isoflavones excreted in urine decreased with increasing intake when expressed as a percentage of the administered dose (63.2 +/- 8.0, 54.4 +/- 8.1 and 44.0 +/- 4.3%, respectively, for daidzein, and correspondingly, 25.2 +/- 5.3, 13.4 +/- 2.1 and 15.8 +/- 2.7% for genistein), underscoring the trend toward nonlinear pharmacokinetics. Equol was identified as a metabolite in 30% of women; it was present consistently in urine and blood from the same subjects. Its delayed appearance was consistent with colonic synthesis. On the basis of the pharmacokinetics, optimum steady-state serum isoflavone concentrations would be expected from modest intakes of soy foods consumed regularly throughout the day rather than from a single highly enriched product.

The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human.

Abstract: Voriconazole is a new triazole antifungal agent with potent, wide-spectrum activity. Its pharmacokinetics and metabolism have been studied in mouse, rat, rabbit, dog, guinea pig, and humans after single and multiple administration by both oral and intravenous routes. Absorption of voriconazole is essentially complete in all species. The elimination of voriconazole is characterized by non-linear pharmacokinetics in all species. Consequently, pharmacokinetic parameters are dependent upon dose, and a superproportional increase in area under the curve is seen with increasing dose in rat and dog toxicology studies. Following multiple administration, there is a decrease in systemic exposure. This is most pronounced in mouse and rat, less so in dog, and not observed in guinea pig or rabbit. Repeat-dose toxicology studies in mouse, rat, and dog have demonstrated that induction of cytochrome P450 by voriconazole (autoinduction of metabolism) is responsible for the decreased exposure in these species. Autoinduction of metabolism is not observed in humans, and plasma steady-state concentrations remain constant with time. Voriconazole is extensively metabolized in all species. The major pathways in humans involve fluoropyrimidine N-oxidation, fluoropyrimidine hydroxylation, and methyl hydroxylation. Also, N-oxidation facilitates cleavage of the molecule, resulting in loss of the fluoropyrimidine moiety and subsequent conjugation with glucuronic acid. Major pathways are represented in animal species. The major circulating metabolite in rat, dog, and human is the N-oxide of voriconazole. It is not thought to contribute to efficacy since it is at least 100-fold less potent than voriconazole against fungal pathogens in vitro.

Pharmacokinetics, Safety, and Tolerability of Oral Posaconazole Administered in Single and Multiple Doses in Healthy Adults

Abstract: The pharmacokinetics, safety, and tolerability of posaconazole, an investigational triazole antifungal, were evaluated following the administration of rising single and multiple oral doses. A total of 103 healthy adults were enrolled in two phase I trials. Each study had a double-blind, placebo-controlled, parallel-group design with a rising single-dose (RSD) or rising multiple-dose (RMD) scheme. In the RSD study, subjects received single doses of posaconazole oral tablets (50 to 1,200 mg) or placebo. In the RMD study, subjects received posaconazole oral tablets (50 to 400 mg) or placebo twice daily for 14 days. By using model-independent methods, the area under the plasma concentration-time curve and the maximum concentration in plasma were determined and used to assess dose proportionality. In the RSD study, the levels of posaconazole in plasma increased proportionally between the 50- and 800-mg dose range, with saturation of absorption occurring above 800 mg. Dose proportionality was also observed in the RMD study. In both studies, the apparent volume of distribution was large (range, 343 to 1,341 liters) and the terminal-phase half-life was long (range, 25 to 31 h). Posaconazole was well tolerated at all dose levels, and the adverse events were not dose dependent. No clinically significant changes in clinical laboratory test values or electrocardiograms were observed. Following the administration of single and twice-daily rising doses, the level of posaconazole exposure increased in a dose-proportional manner. The long elimination-phase half-life of posaconazole supports once- or twice-daily dosing in clinical trials; however, additional studies are required to determine if further division of the dose will enhance exposure.

Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections

Abstract: The pharmacokinetics and pharmacodynamics of linezolid have been extensively investigated in laboratory models, healthy volunteers and patients. Three formulations exist: an intravenous (iv) form, film-coated tablets and an oral suspension. Linezolid can be assayed in serum and body fluids by HPLC and has good bioavailability with a Cmax at 0.5-2 h. The protein binding is 31%, and the volume of distribution is 30-50 L with adequate to good tissue penetration into skin blister fluids, bone, muscle, fat, alveolar cells, lung extracellular lining fluid and CSF. There are two major metabolites of linezolid (PNU-142586 and PNU-142300). Non-enzymic formation of PNU-142586 is the rate-limiting step in the clearance of linezolid, and linezolid and its two main metabolites plus several minor ones are all excreted in the urine. Dose linearity is evident in the Cmax and AUC across a wide range of doses. Gender and age have little effect on pharmacokinetics, but children have greater plasma clearance and volume of distribution and hence, have lower serum concentrations for equivalent doses in adults. No dose modification is needed in mild to moderate liver disease or any degree of renal impairment; however, both PNU-142586 and PNU-142300 accumulate in renal failure. Linezolid is bacteriostatic with a significant post-antibiotic effect against the key pathogens. In animal models of infection, the time the antibiotic concentration exceeds the MIC (t > MIC) helps to determine outcome, and a t > MIC of 40% is predictive of a bacteriostatic effect for both staphylococci and pneumococci. In man, t > MIC and AUC/MIC have been related to bacteriological and clinical outcomes. AUC and length of treatment are also related to the risk of thrombocytopenia.

Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial.

Abstract: Linezolid is the first antibacterial to be approved from the oxazolidinone class. The drug has substantial antimicrobial activity against Gram-positive organisms such as streptococci, staphylococci and enterococci, including species resistant to conventional antibacterial treatment. Linezolid is fully bioavailable following oral administration when compared with intravenous administration. Maximum plasma linezolid concentrations are usually achieved between 1 and 2 hours after oral administration. Food slightly decreases the rate, but not the extent, of absorption. The distribution of linezolid is approximately equivalent to total body water, and there is low protein binding (31%) to serum albumin. The elimination half-life of linezolid is 5–7 hours, and twice-daily administration of 400–600mg provides steady-state concentrations in the therapeutic range. Linezolid is mainly cleared by non-renal clearance to two metabolites and renal clearance of the parent compound. Approximately 50% of an administered dose appears in the urine as the two major metabolites, and approximately 35% appears as parent drug. A small degree of nonlinearity has been observed, with a 30% decrease in clearance after a 5-fold increase in dose. The nonlinearity is not relevant over the therapeutic dosage range. Plasma linezolid concentrations in elderly patients, patients with mild to moderate hepatic impairment or mild to severe renal impairment are similar to those achieved in young or healthy volunteers. Higher concentrations are observed in women as compared with men, but the difference is not sufficient to warrant an adjustment in dosage. In patients with severe renal impairment requiring haemodialysis, the exposure to the two primary metabolites was 7 to 8-fold higher than in patients with normal renal function. Therefore, linezolid should be used with caution in patients with severe renal insufficiency. A higher clearance of linezolid was found in children as compared with adults, and therefore higher daily dosages per kg bodyweight are required in children. There is no pharmacokinetic interaction when linezolid is coadministered with aztreonam, gentamicin or warfarin. Linezolid is a mild, reversible, inhibitor of monoamine oxidases A and B. Coadministration of linezolid with the adrenergic agents pseudoephedrine and phenylpropanolamine resulted in increases in blood pressure relative to these agents alone or to placebo. The degree of the change in blood pressure was within that associated with normal daily activities. No interaction was observed when linezolid was coadministered with the serotonergic agent dextromethorphan.

Modern Pharmacology with Clinical Applications

Abstract: ENERAL PRINCIPLES OF PHARMACOLOGY Mechanisms of Drug Action Drug Absorption and Distribution Metabolism of Drugs Excretion of Drugs Drug Metabolism and Disposition in Pediatric and Gerontological Stages of Life Pharmacokinetics Principles of Toxicology Fundamental and Applied Genetic Toxicology Ethics in Pharmacology: Concepts and Cases Transitions and Progress in Therapeutics DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Introduction to the Autonomic Nervous System Adrenomimetic Drugs Adrenoceptor Antagonists Directly and Indirectly Acting Cholinomimetics Muscarinic Blocking Drugs Ganglionic Blocking Agents DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM Cardiac Glycosides and Other Drugs Used in Myocardial Insufficiency Antiarrhythmic Drugs Antianginal Drugs The Renin-Angiotensin System and Other Vasoactive Substances Calcium Channel Blockers Antihypertensive Drugs Diuretic Drugs Anticoagulant, Antiplatelet, and Fibrinolytic (Thrombolytic) Drugs Cholesterol and Hypocholesterolemic Drugs DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM Introduction to Central Nervous System Pharmacology General Anesthesia: Intravenous and Inhalational Agents Opioid and Nonopioid Analgesics Local Anesthetics Agents Affecting Neuromuscular Transmission Central Nervous System Stimulants Sedative-Hypnotic and Anxiolytic Drugs Drugs Used in Parkinsonism Anticonvulsant Drugs Drugs Used in Mood Disorders Antipsychotic Drugs Contemporary Drug Abuse THERAPEUTIC ASPECTS OF INFLAMMATORY AND SELECTED OTHER CLINICAL DISORDERS Antiinflammatory and Antirheumatic Drugs Drugs Used in Gout Histamine and Histamine Antagonists Drugs Used in Asthma Drugs Used in Gastrointestinal Disorders Drugs Used in Dermatological Disorders Drugs for the Control of Supragingival Plaque CHEMOTHERAPY Introduction to Chemotherapy Synthetic Organic Antimicrobials (Sulfonamides, Trimethorprim, Nitrofurans, Quinolones, Methenamine) ¼-Lactam Antibiotics Aminoglycoside Antibiotics Tetracyclines, Chloramphenicol, Macrolides, and Lincosamides Bacitracin, Glycopeptide Antibiotics, and the Polymyxins Drugs Used in Tuberculosis and Leprosy Antiviral Drugs Drugs Used in Acquired Immunodeficiency Syndrome Antifungal Drugs Antiprotozoal Drugs Antihelmintic Drugs The Rational Basis for Cancer Chemotherapy Antineoplastic Agents Immunomodulating Drugs Gene Therapy DRUGS AFFECTING THE ENDOCRINE SYSTEM Hypothalamic and Pituitary Gland Hormones Adrenocortical Hormones and Drugs Affecting the Adrenal Cortex Estrogens, Progestins, and Antiestrogens Uterine Stimulants and Relaxants Androgens and Anabolic Steroids Thyroid and Antithyroid Drugs Parathyroid Hormone, Calcitonin, and Vitamin D Insulin, Glucagon, Somatostatin, and Orally Effective Hypoglycemic Drugs Vitamin

Pharmacokinetics of L-carnitine.

Abstract: L-Carnitine is a naturally occurring compound that facilitates the transport of fatty acids into mitochondria for beta-oxidation. Exogenous L-carnitine is used clinically for the treatment of carnitine deficiency disorders and a range of other conditions. In humans, the endogenous carnitine pool, which comprises free L-carnitine and a range of short-, medium- and long-chain esters, is maintained by absorption of L-carnitine from dietary sources, biosynthesis within the body and extensive renal tubular reabsorption from glomerular filtrate. In addition, carrier-mediated transport ensures high tissue-to-plasma concentration ratios in tissues that depend critically on fatty acid oxidation. The absorption of L-carnitine after oral administration occurs partly via carrier-mediated transport and partly by passive diffusion. After oral doses of 1-6g, the absolute bioavailability is 5-18%. In contrast, the bioavailability of dietary L-carnitine may be as high as 75%. Therefore, pharmacological or supplemental doses of L-carnitine are absorbed less efficiently than the relatively smaller amounts present within a normal diet.L-Carnitine and its short-chain esters do not bind to plasma proteins and, although blood cells contain L-carnitine, the rate of distribution between erythrocytes and plasma is extremely slow in whole blood. After intravenous administration, the initial distribution volume of L-carnitine is typically about 0.2-0.3 L/kg, which corresponds to extracellular fluid volume. There are at least three distinct pharmacokinetic compartments for L-carnitine, with the slowest equilibrating pool comprising skeletal and cardiac muscle.L-Carnitine is eliminated from the body mainly via urinary excretion. Under baseline conditions, the renal clearance of L-carnitine (1-3 mL/min) is substantially less than glomerular filtration rate (GFR), indicating extensive (98-99%) tubular reabsorption. The threshold concentration for tubular reabsorption (above which the fractional reabsorption begins to decline) is about 40-60 micromol/L, which is similar to the endogenous plasma L-carnitine level. Therefore, the renal clearance of L-carnitine increases after exogenous administration, approaching GFR after high intravenous doses. Patients with primary carnitine deficiency display alterations in the renal handling of L-carnitine and/or the transport of the compound into muscle tissue. Similarly, many forms of secondary carnitine deficiency, including some drug-induced disorders, arise from impaired renal tubular reabsorption. Patients with end-stage renal disease undergoing dialysis can develop a secondary carnitine deficiency due to the unrestricted loss of L-carnitine through the dialyser, and L-carnitine has been used for treatment of some patients during long-term haemodialysis. Recent studies have started to shed light on the pharmacokinetics of L-carnitine when used in haemodialysis patients.

Bioavailability of dexmedetomidine after extravascular doses in healthy subjects.

Abstract: Aim To determine the absolute bioavailability of extravascularly administered dexmedetomidine, a novel a2-adrenoceptor agonist, in healthy subjects. Methods Single 2 µg kg−1 doses of dexmedetomidine were given intravenously, intramuscularly, perorally and buccally (where the solution is not swallowed) to 12 healthy male subjects. The drug concentration-time data were analysed using linear one-compartment (buccal and peroral data), or two-compartment modelling (intravenous data), or noncompartmental methods (intramuscular data). Results Mean (95% CI) absolute bioavailability after peroral, buccal and intramuscular administration was 16% (12–20%), 82% (73–92%) and 104% (96–112%), respectively. Conclusion Dexmedetomidine is well absorbed systemically through the oral mucosa, and therefore buccal dosing may provide an effective, noninvasive route to administer the drug.

Role of variability in explaining ethanol pharmacokinetics: research and forensic applications.

Abstract: Variability in the rate and extent of absorption, distribution and elimination of ethanol has important ramifications in clinical and legal medicine. The speed of absorption of ethanol from the gut depends on time of day, drinking pattern, dosage form, concentration of ethanol in the beverage, and particularly the fed or fasting state of the individual. During the absorption phase, a concentration gradient exists between the stomach, portal vein and the peripheral venous circulation. First-pass metabolism and bioavailability are difficult to assess because of dose-, time- and flow-dependent kinetics. Ethanol is transported by the bloodstream to all parts of the body. The rate of equilibration is governed by the ratio of blood flow to tissue mass. Arterial and venous concentrations differ as a function of time after drinking. Ethanol has low solubility in lipids and does not bind to plasma proteins, so volume of distribution is closely related to the amount of water in the body, contributing to sex- and age-related differences in disposition. The bulk of ethanol ingested (95-98%) is metabolised and the remainder is excreted in breath, urine and sweat. The rate-limiting step in oxidation is conversion of ethanol into acetaldehyde by cytosolic alcohol dehydrogenase (ADH), which has a low Michaelis-Menten constant (Km) of 0.05-0.1 g/L. Moreover, this enzyme displays polymorphism, which accounts for racial and ethnic variations in pharmacokinetics. When a moderate dose is ingested, zero-order elimination operates for a large part of the blood-concentration time course, since ADH quickly becomes saturated. Another ethanol-metabolising enzyme, cytochrome P450 2E1, has a higher Km (0.5-0.8 g/L) and is also inducible, so that the clearance of ethanol is increased in heavy drinkers. Study design influences variability in blood ethanol pharmacokinetics. Oral or intravenous administration, or fed or fasted state, might require different pharmacokinetic models. Recent work supports the need for multicompartment models to describe the disposition of ethanol instead of the traditional one-compartment model with zero-order elimination. Moreover, appropriate statistical analysis is needed to isolate between- and within-subject components of variation. Samples at low blood ethanol concentrations improve the estimation of parameters and reduce variability. Variability in ethanol pharmacokinetics stems from a combination of both genetic and environmental factors, and also from the nonlinear nature of ethanol disposition, experimental design, subject selection strategy and dose dependency. More work is needed to document variability in ethanol pharmacokinetics in real-world situations.

Toxicity pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study

Abstract: OBJECTIVE: To evaluate the safety and pharmacokinetics of multiple infusions of a humanized anti-interleukin-6 (IL-6) receptor antibody, MRA, in patients with rheumatoid arthritis (RA). METHODS: In an open label trial, 15 patients with active RA were intravenously administered 3 doses (2, 4, or 8 mg/kg) of MRA biweekly for 6 weeks, and pharmacokinetics were assessed. Patients continued on MRA treatment for 24 weeks, and were then assessed for safety and efficacy. RESULTS: The treatment was well tolerated at all doses with no severe adverse event. Increased total serum cholesterol was detected as an MRA related reaction in 10/15 (66%) patients. There was no statistically significant difference in the frequency of adverse events among the 3 dose groups. There were no new observations of antinuclear antibody or anti-DNA antibody, and no anti-MRA antibody was detected. The T1/2 increased with repeated doses and as the dose increased. T1/2 after the 3rd dose of 8 mg/kg reached 241.8 +/- 71.4 h. In 12/15 (80%) patients whose serum MRA was detectable during the treatment period, objective inflammatory indicators such as C-reactive protein, erythrocyte sedimentation rate, and serum amyloid A were completely normalized at 6 weeks, although there was no statistically significant difference in efficacy among the 3 dose groups. Nine of 15 patients achieved ACR 20 at 6 weeks. At 24 weeks, 13 patients achieved ACR 20 and 5 achieved ACR 50. CONCLUSION: Repetitive treatment with MRA was safe and normalized acute phase response in patients with RA. Optimal dosing schedule was not defined in this small study, but maintenance of serum MRA concentration seemed important to achieve efficacy.

Clinical Pharmacokinetic Profile of Modafinil

Abstract: Modafinil is a unique wake-promoting agent for oral administration. Its pharmacological properties are distinct from those of other CNS agents, and it selectively targets neuronal pathways in the sleep/wake centres of the brain. After single or multiple oral doses, modafinil is readily absorbed, reaching maximum plasma concentrations at 2-4 hours after administration and pharmacokinetic steady state within 2-4 days. Its pharmacokinetics are dose-independent between 200 and 600 mg/day. The elimination half-life is approximately 12-15 hours, which is largely reflective of the pharmacokinetics of the longer-lived l-enantiomer. Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine. Less than 10% of the dose is excreted as unchanged drug. Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways. In patients who are renally or hepatically compromised, the elimination processes can be slowed, and in a similar manner (although to a lesser extent), elimination in the elderly may be reduced due to normal effects of aging. Because modafinil is administered concomitantly with other medications, the potential for metabolic drug-drug interactions has been examined both in vitro and in vivo. In vitro, modafinil was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small, but concentration-dependent, induction of CYP1A2, CYP2B6 and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes. Clinical studies have been conducted to examine the potential for interactions with methylphenidate, dexamfetamine, warfarin, ethinylestradiol and triazolam. The only substantive interactions observed were with ethinylestradiol and triazolam, apparently through induction of CYP3A4, primarily in the gastrointestinal system. Overall, the results of the interaction studies suggest that modafinil has potential to affect the pharmacokinetics of drugs that are metabolised by certain CYP enzymes. Compounds that induce or inhibit CYP activity are unlikely to have major effects on the pharmacokinetics of modafinil. In summary, the results show that modafinil is a moderately long-lived drug that is well absorbed and extensively metabolised.

Eflornithine for the treatment of human African trypanosomiasis.

Abstract: Eflornithine is the only new molecule registered for the treatment of human African trypanosomiasis over the last 50 years. It is the drug used mainly as a back-up for melarsoprol refractory Trypanosoma brucei gambiense cases. The most commonly used dosage regimen for the treatment of T. b. gambiense sleeping sickness consists of 100 mg kg–1 body weight at intervals of 6 h for 14 days (150 mg kg–1 body weight in children) of eflornithine given as short infusions. Its efficacy against Trypanosoma brucei rhodesiense is limited due to the innate lack of susceptibility of this parasite based on a higher ornithine decarboxylase turnover. Adverse drug reactions during eflornithine therapy are frequent and the characteristics are similar to other cytotoxic drugs for the treatment of cancer. Their occurrence and intensity increase with the duration of treatment and the severity of the general condition of the patient. Generally, adverse reactions to eflornithine are reversible after the end of treatment. They include convulsions (7%), gastrointestinal symptoms like nausea, vomiting and diarrhea (10%–39%), bone marrow toxicity leading to anemia, leucopenia and thrombocytopenia (25–50%), hearing impairment (5% in cancer patients) and alopecia (5–10%). The drug arrests embryonic development in mice, rats and rabbits but the extent of excretion into breast milk is unknown. The mean half-life is around 3–4 h and the volume of distribution in the range of 0.35 l kg–1. Renal clearance is about 2 ml min kg–1 (i.v.) and accounts for more than 80% of drug elimination. Bioavailability of an orally administered 10 mg kg–1 dose was estimated at 54%. One of the major determinants of successful treatment seems to be the cerebrospinal fluid drug level reached during treatment, and it was shown that levels above 50 µmol l–1 must be reached to attain the consistent clearance of parasites. Based on its trypanostatic rather than trypanocidal mode of action, it is a rather slow-acting drug.