Reduction In First-pass Metabolism Research Articles

Pharmacokinetic Considerations in Geriatric Medication

Aging have an impact on the pharmacokinetic and pharmacodynamic characteristics of drugs, resulting in clinically relevant safety and efficacy consequences. There appear to be a rise in gastrointestinal (GI) problems with age, and certain slight variations in the GI tract have been noted. Nevertheless, insufficient studies have been done on the impact of aging on the expression and activity of these GI transporters. Aging is associated with some reduction in first-pass metabolism that might be due to a decrease in liver mass and perfusion. Some medications with considerable first-pass metabolism, can have markedly enhanced bioavailability and, as a consequence bioavailability. Other high clearance (CL) medications have identical bioavailability in both young and old individuals. However, at the other hand, the first-pass activation of some prodrugs, may be slowed or decreased, leading to a reduction in bioavailability. Some drugs may have a low bioavailability when taken orally, benefitted from transdermal administration. There are still no specific age-related liver ailments, routine clinical tests of liver function do not vary substantially with age, the course, and outcome of some liver diseases can be affected by age. The characteristic of high or low extraction of a drug by the liver has been attributed to whether the metabolic clearance (CL) of a drug falls or remains unchanged with age. Reduction in renal function in elderly subjects, particularly glomerular filtration rate, affects the clearance of many drugs such as water-soluble antibiotics and nonsteroidal anti-inflammatory drugs. The therapeutic significance of these declines in renal excretion is governed by the drug's expected toxicity. Many drugs show their effects specially in old age patients in different manner and depend on age related factors. It must take appropriate precautions for administering of different drugs to the old age patients.

In vitro/in vivo evaluation of an optimized fast dissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylic acids

Improvement of water solubility, dissolution rate, oral bioavailability, and reduction of first pass metabolism of OL (OL), were the aims of this research. Co-amorphization of OL carboxylic acid dispersions at various molar ratios was carried out using rapid solvent evaporation. Characterization of the dispersions was performed using differential scanning calorimetry (DSC), Fourier transform infrared spectrometry (FTIR), X-ray diffractometry (XRD), and scanning electron microscopy (SEM). Dispersions with highest equilibrium solubility were formulated as fast dissolving oral films. Modeling and optimization of film formation were undertaken using artificial neural networks (ANNs). The results indicated co-amorphization of OL-ascorbic acid through H-bonding. The co-amorphous dispersions at 1:2 molar ratio showed more than 600-fold increase in solubility of OL. The model optimized fast dissolving film prepared from the dispersion was physically and chemically stable, demonstrated short disintegration time (8.5 s), fast dissolution (97% in 10 min) and optimum tensile strength (4.9 N/cm2). The results of in vivo data indicated high bioavailability (144 ng h/mL) and maximum plasma concentration (14.2 ng/mL) compared with the marketed references. Therefore, the optimized co-amorphous OL-ascorbic acid fast dissolving film could be a valuable solution for enhancing the physicochemical and pharmacokinetic properties of OL.

Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects

AIMTo determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution or increased clearance.METHODSIn a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i.v. artesunate (i.v. ARS) (4 mg kg−1) on the first day and oral ARS (4 mg kg−1) on the second, or, oral on the first and i.v. on the second, in both groups followed by oral ARS (4 mg kg−1 day−1) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (3 months post partum).RESULTSI.v. ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n = 20) and in controls (n = 14). Oral administration resulted in higher total drug exposure in pregnancy [AUC (95% CI) in (ng ml−1 h)/(mg kg−1)] of 55.1 (30.1, 100.0) vs. 26.5 (12.2, 54.3) for ARS, P = 0.002 and 673 (386, 1130) vs. 523 (351, 724) for DHA, P = 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6, 75.1) vs. 9.9 (6.0, 36.81) for ARS (P = 0.046) and 77.0 (42.2, 129) vs. 72.7 (42.0, 87.7) for DHA, P = 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared with day 0 or 1, but not in the controls (P = 0.084).CONCLUSIONSThis study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data are reassuring regarding current dosing recommendations.

Age-Related Changes in Pharmacokinetics

Ageing is characterized by a progressive decline in the functional reserve of multiple organs and systems, which can influence drug disposition. In addition, comorbidity and polypharmacy are highly prevalent in the elderly. As ageing is associated with some reduction in first-pass metabolism, bioavailability of a few drugs can be increased. With ageing body fat increases and total body water as well as lean body mass decrease. Consequently, hydrophilic drugs have a smaller apparent volume of distribution (V) and lipophilic drugs have an increased V with a prolonged half-life. Drugs with a high hepatic extraction ratio display some age-related decrease in systemic clearance (CL), but for most drugs with a low hepatic extraction ratio, CL is not reduced with advancing age. In general, activities of cytochrome P450 enzymes are preserved in normal ageing and the genetic influence is much more striking than age effects. Drug transporters play an important role in pharmacokinetic processes, but their function and pharmacology have not yet been fully examined for agerelated effects. One third of elderly persons show no decrease in renal function (GFR > 70 mL/min/1.73 m2). In about two thirds of elderly subjects, the age-related decline of renal function was associated with coexisting cardiovascular diseases and other risk factors. In the elderly a large interindividual variability in drug disposition is particularly prominent. In conclusion, the complexity of interactions between comorbidity, polypharmacy, and age-related changes in pharmacokinetics (and pharmacodynamics) justify the old and well-known dosing aphorism " start low, go slow" for aged individuals.

SELF EMULSIFYING DRUG DELIVERY SYSTEM

Self-micro emulsifying drug delivery systems (SMEDDS) indicate the formulations forming transparent micro emulsions with oil droplets ranging between 100 nm and 250 nm. The Lipid Formulation Classification System was introduced as a working model in 2000, and an extra ‘type’ of formulation was added in 2006. Self-emulsification takes place when the entropy change favouring dispersion is greater than the energy required to increase the surface area of the dispersion. For highly lipophilic drugs, lipids may enhance the extent of lymphatic transport and increase bioavailability directly or indirectly via reduction in first pass metabolism. The polarity of the lipid phase is one of the main factors that govern the drug release from the micro-emulsions. If surfactant or co-surfactant is contributing to the greater extent in drug solubilization then there could be a risk of precipitation, as dilution of SMEDDS will lead to lowering or solvent capacity of the surfactant or co-surfactant.

Intestinal Lymphatic Transport Enhances the Post-Prandial Oral Bioavailability of a Novel Cannabinoid Receptor Agonist Via Avoidance of First-Pass Metabolism

To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs. Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13. Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3-4.9 fold increase in AUC(0 - infinity)) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8-20%), in spite of good absorption (72-75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system. The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first examples of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism.

Minimizing Bioavailability Variations with Oral Controlled Release Formulations

Despite various routes of drug delivery being explored, the oral route has continued to be the most popular route of drug administration. However, the complexities associated with the gastrointestinal tract lead to variations in the rate and extent of bioavailability of drugs administered as oral dosage forms. This variation in the bioavailability of drugs is responsible for the majority of adverse effects, lack of efficacy, and development of tolerance, etc. This review explores the possibilities of minimizing these bioavailability variations with the use of oral controlled release (CR) dosage forms. The use of CR preparations, in lieu of the immediate preparations in itself, leads to better control over plasma levels. Furthermore, the additional benefits offered by CR products, such as the reduction in first-pass metabolism, enhanced and reproducible bioavailability with gastro retentive preparations, overcoming circadian rhythm variations, and the lesser effect of fed condition on bioavailability, can be effectively utilized for bioavailability variation minimization. However, CR products cannot be use indiscriminately. The use of CR products to serve the purpose of bioavailability variation minimization should be based on due consideration to the role of metabolizing enzymes, the permeability variations, and the area available for absorption.

Pharmacokinetic analysis of absorption and metabolism of dopamine and a dopamine prodrug in dogs

Pharmacokinetic compartment models were constructed to describe the absorption and metabolism of dopamine (DA) and DA prodrug, N-(N-acetyl-L-methionyl)0,0-bis-eth-oxycarbonyl) dopamine(1). Plasma concentrations of DA, DA-SO4, and DOPAC after oral administration of DA to dogs, were analysed using the pharmacokinetic model assuming the contribution of first-pass metabolism for the formation of DA-SO4 and DOPAC. Though plasma concentration of DA was quite different from that of DA-SO4 or DOPAC, these data were simultaneously analysed with a good fitting curve. The apparent absorption rate constant of DA(K1) was proved to be much smaller than the apparent formation rate constants of DA-SO4(K2) or DOPAC(K3). It was found that the compartment model is useful for the evaluation of absorption and metabolic inactivation of DA. Plasma concentration of DA, N-(N-acetyl-L-methionyl)dopamine(2), DA-SO4, and DOPAC after oral administration of 1 were simultaneously analysed using the compartment model including the first-pass metabolism and two-fraction dissolution process. Good fitting curves were obtained. The apparent formation rate constant of 2(K4) is larger than that of DA-SO4(K5) or DOPAC(K6); thus it was shown that two protective groups of 1 reduced the metabolism of DA and 2 specially played an important role to the reduction of first-pass metabolism. From these results, it was found to be possible to give a pharmacokinetic interpretation for the mechanism of reduction of first-pass metabolism of DA.

Reduction of first-pass metabolism of propranolol after oral administration of ester prodrugs

For orally administered drugs, first=pass metabolism by the liver is a formidable barrier to efficient delivery. Extensive first-pass metabolism, in addition to decreasing the percentage of dose reaching its intended site of action, often leads to significant variability in bioavailability, necessitating careful monitoring of patient blood levels. While first-pass metabolism can be avoided by selecting alternate routes of administration (i.v., transdermal, rectal, etc.), the oral route is generally preferred. Rational approaches for minimizing first-pass metabolism would therefore be quite valuable. Propranolol, used extensively in the treatment of angina pectoris, hypertension, and cardiac arrhythmia, has been shown to undergo extensive presystemic metabolism after oral administration leading to reduced bioavailabihty (Paterson et al., 1970; Shand et al., 1970; Lo et al., 1982) and significant inter-subject variability in blood levels (Kornhauser et al., 1978). Garceau et al. (1978) have shown that the hemisuccinate ester of propranolol, when administered orally to beagle dogs, yields propranolol levels 8 times higher than after an equivalent dose of propranolol hydrochloride.

Effects of hydralazine, nitroglycerin, and food on estimated hepatic blood flow.

Several recent studies have shown that hydralazine and nitroglycerin may increase the apparent oral bioavailability of high-clearance drugs. It has been postulated that the mechanism responsible may be a vasodilator-induced transient increase in hepatic blood flow with an associated reduction in first-pass metabolism. To test this hypothesis, we examined the effect of hydralazine (25 mg) and sublingual nitroglycerin (2 doses of 0.6 mg separated by 30 minutes) on indocyanine green (ICG) blood clearance (ClB). Forty minutes after the start of nitroglycerin therapy, ICG ClB fell from a baseline of 648 +/- 98 to 607 +/- 151 ml/min, and was further decreased to 578 +/- 98 ml/min 80 minutes after dosing. Hydralazine induced no consistent effect on ICG ClB. ICG ClB was 744 +/- 376, 721 +/- 218, and 763 +/- 195 ml/min at baseline, 40 minutes, and 80 minutes after dosing. As a positive control, ICG ClB was assessed after a high-protein meal. After this meal, ICG ClB increased from 656 +/- 107 to 811 +/- 141 and 801 +/- 132 ml/min at 40 and 80 minutes after dosing. These data suggest that one or more mechanism(s) other than changes in hepatic blood flow are involved in the vasodilator-induced increase in the apparent oral bioavailability of high-clearance drugs.