Dual Elimination Research Articles

Bivalirudin: a review of the pharmacology and clinical application

Among the current agents in the class of direct thrombin inhibitors, bivalirudin (Angiomax®, The Medicines Company, NJ, USA) has seen increased use in cardiovascular medicine over the past decade through its primary indication as an anticoagulant used during percutaneous coronary interventions. Bivalirudin has been further investigated and used as the anticoagulation strategy in the setting of cardiac and endovascular surgical procedures and is frequently utilized in the management of patients with heparin-induced thrombocytopenia. In comparison with heparin, bivalirudin exhibits a low immunogenic profile and provides similar or reduced major bleeding rates as well as a predictable degree of anticoagulation that is dose related. Bivalirudin primarily undergoes dual elimination via proteolytic cleavage and renal elimination, and requires dose adjustment in the setting of severe renal dysfunction. Given the body of supportive data, bivalirudin is likely to continue to figure prominently as a reliable and efficient anticoagulation strategy. Additional agents in the class of direct thrombin inhibitors are under investigation and may find increasing clinical use.

Morphine to Methadone Conversion: An Interpretation of Published Data

For the past 20 years, methadone has been experiencing resurgence in the palliative care community as a second-line opioid for the treatment of cancer pain. The advantages of using methadone for refractory pain in patients with cancer or in those who could not tolerate the side effects of other opioids such as morphine are well cited in recent literature. Advantages of methadone over other opioids include dual elimination without active metabolites, allowing safe use with renal and liver failure, N-methyl-D-aspartate (NMDA) and delta receptor activity in addition to mu receptor agonism, multiple routes of administration, rapid onset of action, long half-life, low cost, and fewer adverse effects. Despite the abundance of recent case reports and literature reviews demonstrating the effective use of methadone in patients with cancer, there is a lack of consensus for an appropriate method for converting morphine (and by extension, other opioids) to methadone. This article will review methadone pharmacology and multiple proposed conversion methods; a case report illustrating a popular method for high-dose conversion is also included.

Metabolic syndrome and role of ACE inhibitors in its management: focus on trandolapril

The review describes modern view in metabolic syndrome, diagnostic criteria and management. ACE inhibitors are shown to be indicated to such patients. Trandolapril due to its significant advantages - long duration of action, dual elimination and high tissue activity can be considered predominantly indicated to patients with metabolic syndrome.

Development of liquid chromatographic method for fosinoprilat determination in human plasma using microemulsion as eluent

Fosinopril sodium presents a prodrug for the active angiotensin converting enzyme (ACE) inhibitor, fosinoprilat. The dual elimination of fosinoprilat by the liver and the kidney distinguishes fosinopril from other angiotensin converting enzyme inhibitors. Such ways of elimination are important for antihypertensive therapy of patients on haemodialysis. The paper presents development and evaluation of a new and sensitive liquid chromatographic (LC) method for the analysis of fosinoprilat in plasma obtained from patients on haemodialysis. A microemulsion system mixture as mobile phase has been used for the separation and analysis of fosinoprilat in plasma samples. The plasma samples were injected directly onto the HPLC system (Waters Breeze) after appropriate sample dilution with mobile phase. Separations were performed on the Bakerbond ENV 4.6 mm × 150 mm, 5 μm particle size column with UV detection at 220 nm. The flow rate was 1.00 mL min −1. The mobile phase consisted of 1.0% (w/v) of diisopropyl ether, 2.0% (w/v) of sodium dodecyl sulphate (SDS), 6.0% (w/v) of n-propanol and 91% (w/v) of aqueous 25 mM di-sodium hydrogen phosphate, pH adjusted to 2.8 with 85% orthophosphoric acid. The developed method was then subjected to method validation according to the criteria stated in the FDA bioanalytical method validation guidance. The results for specificity, linearity, low limit of quantification (LLOQ), precision, accuracy and stability were within the accepted criteria. The unique approach applied in this paper makes possible the determination of fosinoprilat even in the presence of metabolites of other drugs, so the method can be used for obtaining the reliable results in a fast and simple way.

The Construction of the Automatic Quadrilateral Mesh Generation System for the Hexahedral Mesh Generation : 1st Report, Proposal of the Algorithm

Recently the dual cycle elimination method was proposed by Muller-Hannemann for hexahedral mesh generation. This method starts with a surface quadrilateral mesh whose dual cycles have no self-intersections and, after the elimination of dual cycles, generates a hexahedral mesh while tracing back the reverse order of eliminations and supplementing hexahedrons inside the object step by step. This paper concerns with the automatic quadrilateral mesh generation system for the dual-cycle elimination method. We shall propose a simple method to construct such a surface mesh for a given polyhedron and nodes on its edges. Some kinds of templates play an important role on our method.

Pharmacokinetics of Intravenous Alcohol: Two Compartment, Dual Michaelis-Menten Elimination

Alcoholism: Clinical and Experimental ResearchVolume 24, Issue 4 p. 424-425 Pharmacokinetics of Intravenous Alcohol: Two Compartment, Dual Michaelis-Menten Elimination Susan E. Shoaf, Corresponding Author Susan E. Shoaf Unit of Phamacokinetic Studies, Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.Reprint requests: Susan Shoaf, M.D., OTSUKA American Pharmaceuticals, 2440 Research Blvd., Rockville, MD 20850; Fax: 301-721-7127; E-mail: susans@mocr.oapi.comSearch for more papers by this author Susan E. Shoaf, Corresponding Author Susan E. Shoaf Unit of Phamacokinetic Studies, Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.Reprint requests: Susan Shoaf, M.D., OTSUKA American Pharmaceuticals, 2440 Research Blvd., Rockville, MD 20850; Fax: 301-721-7127; E-mail: susans@mocr.oapi.comSearch for more papers by this author First published: 11 April 2006 https://doi.org/10.1111/j.1530-0277.2000.tb02007.xCitations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume24, Issue4April 2000Pages 424-425 RelatedInformation

Pharmacokinetics of Intravenous Alcohol: Two Compartment, Dual Michaelis-Menten Elimination

Pharmacokinetics of Intravenous Alcohol: Two Compartment, Dual Michaelis-Menten Elimination

Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors?

Information from clinical and pharmacokinetic studies of angiotensin-converting enzyme inhibitors (ACEIs) has come from subjects who are mostly male and Caucasian, but the use of ACEIs extends to populations worldwide. Significant differences between Chinese in general and male Caucasians have been demonstrated in the pharmacokinetics/dynamics of other drug classes that could have implications for the use of ACEIs in the Chinese population. These include: significant Chinese/Caucasian genetic variation in the renin-angiotensin system based on an insertion/deletion (O/D) polymorphism of the ACE gene; the genetic determination of plasma ACE activity in the Chinese population; and genetic factors involving the disease substrate which may also influence the response to treatment. Oral and IV pharmacokinetic data from various studies of Chinese and Caucasian subjects are available for cilazapril, fosinopril, and perindopril, and pharmacodynamic data are available for eight different ACEIs. Based on these data, there are few differences among the pharmacokinetics of ACEIs between Chinese and Caucasians. Most ACEIs showed good blood pressure lowering efficacy in Chinese (benazepril, enalapril, fosinopril and spirapril), with perhaps less blood pressure lowering with cilazapril or a relatively shorter-term effect with cilazapril or perindopril compared to Caucasions. Chinese experience more cough from ACEIs (captopril and enalapril) than Caucasians. Data suggest that fosinopril may not induce cough in as many subjects as other ACEIs, and this seems to be true of Chinese as well. The mechanism, currently unknown, could involve fosinopril's dual elimination pathway (hepatic and renal). Pharmacokinetic data also support the use of fosinopril in congestive heart failure where elimination pathways may be impaired. In conclusion, ethnic differences between Chinese and Caucasians with respect to ACE and AGT gene polymorphism, which might be expected to differentially affect the action of ACEIs in these two ethnic groups, do not, in fact, have such an effect. Rather, differences among the ACEIs appear to be more important. Journal of Human Hypertension (2000) 14, 163-170.

Hexahedral Mesh Generation by Successive Dual Cycle Elimination

We propose a new method for constructing all-hexahedral finite element meshes. The core of our method is to build up a compatible combinatorial cell complex of hexahedra for a solid body which is topologically a ball, and for which a quadrilateral surface mesh of a certain structure is prescribed. The step-wise creation of the hex complex is guided by the cycle structure of the combinatorial dual of the surface mesh. Our method transforms the graph of the surface mesh iteratively by changing the dual cycle structure until we get the surface mesh of a single hexahedron. Starting with a single hexahedron and reversing the order of the graph transformations, each transformation step can be interpreted as adding one or more hexahedra to the so far created hex complex. Given an arbitrary solid body, we first decompose it into simpler subdomains equivalent to topological balls by adding virtual 2-manifolds. Secondly, we determine a compatible quadrilateral surface mesh for all subdomains created. Then, in the main part we can use the core routine to build up a hex complex for each subdomain independently. The embedding and smoothing of the combinatorial mesh(es) finishes the mesh generation process. First results obtained for complex geometries are encouraging.

Pharmacokinetics of Fosinopril and Hydrochlorothiazide in Healthy Elderly and Young Men

Objective: This study evaluated the effect of advanced age on the single-dose and steady-state pharmacokinetics of the angiotensin converting enzyme inhibitor fosinopril along with the diuretic hydrochlorothiazide. Design and Setting: Open-label, multiple-dose study in a hospital-based clinical study unit. Study Participants: Twelve young (21 to 30 years) and 12 elderly (66 to 75 years) healthy men. Interventions: Participants received a combination tablet of fosinopril 20mg and hydrochlorothiazide (HCTZ) 12.5mg as a single daily dose for a total of 6 doses. Drug concentrations were measured on days 1 and 7 by radioimmunoassay (fosinoprilat, the active diacid) and by HPLC (HCTZ) for calculation of first-dose and steady-state pharmacokinetic parameters. Results: Fosinoprilat steady-state maximum serum concentration (Cmax) was somewhat higher in the elderly, but area under the serum concentration-time curve (AUC) and other pharmacokinetic parameters were similar in the young and elderly adults. As expected with age-related diminished renal function, HCTZ clearance was lower in the elderly, while its cumulative urinary excretion was similar in the two groups. Conclusion: Advanced age is not accompanied by a clinically meaningful change in the pharmacokinetic profiles of fosinopril and HCTZ and does not warrant dose adjustment based on advanced age alone. The favourable pharmacokinetic feature of fosinopril of having dual (renal and hepatic) and compensatory elimination pathways is preserved in the elderly during combination therapy with HCTZ.

Fosinopril. A review of its pharmacology and clinical efficacy in the management of heart failure.

Fosinopril is the prodrug of the active diacid ACE inhibitor fosinoprilat. In patients with heart failure, fosinopril reduces pulmonary capillary wedge pressure, mean arterial blood pressure, mean right atrial pressure and heart rate, and increases stroke volume index and cardiac index. The drug has compensatory dual elimination routes via renal and hepatic systems and accumulates to a lesser extent than enalapril and lisinopril in patients with chronic renal insufficiency with or without heart failure. Comparative studies of 3 or 6 months' duration with fosinopril 10 to 40 mg/day have demonstrated clinical efficacy significantly superior to that of placebo in patients with heart failure [mostly New York Heart Association (NYHA) functional class II or III]. Fosinopril treatment consistently increased exercise duration and improved heart failure symptoms in these patients. Significantly fewer fosinopril than placebo recipients withdrew or were hospitalised because of worsening heart failure. Additionally, significantly more fosinopril than placebo recipients showed improvement, and fewer patients had deteriorated, in terms of NYHA functional class. Fosinopril and enalapril showed similar clinical efficacy over 6 and 12 months' treatment in patients with NYHA functional class II to IV heart failure. As yet, there are no data showing a mortality benefit with fosinopril. Fosinopril was well tolerated in clinical trials in patients with heart failure. Dizziness (11.9 vs 5.4% for placebo), cough (9.7 vs 5.1%) and hypotension (4.4 vs 0.8%) were the most commonly reported adverse events. In 6- or 12-month comparative studies, fosinopril therapy was associated with a lower incidence of dizziness and hypotension, but a higher incidence of vertigo, than enalapril therapy. 0.8% of patients discontinued the drug because of cough, which occurred to a similar extent with fosinopril and enalapril. Thus, based on available clinical evidence, fosinopril is an effective and well tolerated option for the management of patients with heart failure. Although clinical data are limited, fosinopril may be especially useful in patients with renal or hepatic impairment.

Fosinopril: a reappraisal of its pharmacology and therapeutic efficacy in essential hypertension.

Fosinopril is a phosphinic acid derivative which undergoes rapid hydrolysis after oral administration to the active diacid ACE inhibitor fosinoprilat. Cardiotropic effects have been associated with the drug, and the compensatory dual elimination route of fosinopril via renal and hepatic systems offers an opportunity for ACE inhibitor treatment of hypertension in patients with renal or hepatic impairment. Comparative trials of monotherapy with fosinopril 10 to 40 mg/day have demonstrated antihypertensive efficacy equivalent to that of sustained release nifedipine 40 mg/day, hydrochlorothiazide 25 to 50 mg/day, enalapril 5 to 10 mg/day amlodipine 5 to 10 mg/day and sustained release verapamil 240 to 480 mg/day, and superior to that of isradipine 5 mg/day. The efficacy of combination therapy with fosinopril 10 to 20 mg/day and hydrochlorothiazide 12.5 mg/day was significantly superior to that of hydrochlorothiazide alone, tended to be superior to that of fosinopril 20 mg/day alone and was similar to that of sustained release nifedipine 40 mg/day alone. The combination of fosinopril/chlorthalidone 20 to 40/25 mg/day was as effective as propranolol/chlorthalidone 80 to 160/25 mg/day. The incidence of adverse effects associated with fosinopril is low, and cough may possibly occur less often with this drug than with other ACE inhibitors. Fosinopril thus offers an effective and well tolerated option for the treatment of hypertension in adult and elderly patients, including those with renal or hepatic impairment.

Two-stage solution for framed tube buildings

A two-stage solution procedure is presented for the lateral load analysis of framed tubes. In the first stage dual shape functions and Gauss elimination solution are used to obtain an approximate solution. In the second stage a Gauss-Seidel iterative solution is used to obtain an accurate solution. The proposed two-stage solution procedure only requires a small fraction of the CPU time needed in the standard Gauss elimination solution. Computer storage locations required are also smaller than those in the standard solution. With the use of the two-stage solution procedure analysis of framed tubes of practical sizes can be carried out on PCs.

Gadolinium-Ethoxybenzyl-DTPA, a New Liver-Specific Magnetic Resonance Contrast Agent: Kinetic and Enhancement Patterns in Normal and Cholestatic Rats

Gadolinium-ethoxybenzyl-DTPA (Gd-EOB-DTPA) is a new hepatobiliary magnetic resonance imaging (MRI) contrast agent with a dual elimination: 70% via the liver and bile and 30% via the kidney in normal rats. The abdominal enhancement patterns of this new compound and the uptake mechanism by the liver were studied in rats using tissue relaxometry and MRI. Twelve normal rats, 33 rats treated with agents designed to inhibit biliary excretion of the agent, and 6 rats with surgically ligated common bile ducts received Gd-EOB-DTPA intravenously. Distribution and excretion were measured by MR relaxometry. MR signal intensity was measured over time for liver, kidney, and bowel. In normal animals, 0.1 mmol/kg Gd-EOB-DTPA induced a significantly greater (200%) and more prolonged liver signal enhancement (100% at 30 minutes) than Gd-DTPA at the same dose. Either hyperbilirubinemia, induced by common bile duct ligation, or bromosulfophtalein (BSP) infusion inhibited liver uptake of Gd-EOB-DTPA, resulting in a preferential elimination via the kidney. Taurocholate (TC), an inhibitor of the bile acid transporter, was unable to block the liver uptake of Gd-EOB-DTPA. Blood half-lives of Gd-EOB-DTPA in rats were 2.4 minutes for the first component and 8.2 minutes for the second. Data indicate that transport of Gd-EOB-DTPA through the liver into bile is driven by the organic anion transporter. The relation between enhancement of liver and kidney may be diagnostically useful to indirectly evaluate liver excretory function. Yet, persistent enhancement of liver, even in the presence of severe hyperbilirubinemia, should be sufficient to identify focal mass lesions.

Renal handling of enalaprilat.

Most converting enzyme inhibitors share a predominantly renal dual elimination pathway consisting of glomerular filtration and tubular secretion. Since enalaprilat has two functional acidic groups, it is likely that it may be secreted via the proximal tubule organic acid system and, thus, its clearances would exceed that of glomerular filtration rate markers. We therefore examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances to explore the contribution of tubular secretion to the renal elimination of the drug. Twelve healthy male subjects with an age range of 24 to 58 years (mean +/- SE, 33.1 +/- 2.8) were studied. They had representative height (178.6 +/- 1.99 cm) and weight (73.3 +/- 2.1 kg) and had normal renal function as judged by blood urea nitrogen (BUN) (6 +/- 0.3 mmol/L [17 +/- 0.8 mg/dL]), plasma creatinine (88 +/- 3 mumol/L [1.0 +/- 0.03 mg/dL]), and creatinine clearance determined by a prestudy 24-hour urine collection (123.2 +/- 6.2 mL/min). Results are as follows: mean creatinine clearance, 2.12 mL/s (127 mL/min); mean inulin clearance, 119.1 ml/min mean creatinine clearance/inulin clearance, 1.07 mean enalaprilat protein binding, 37.9% unbound enalaprilat clearance, 222.4 ml/min; and the mean fractional enalaprilat clearances were: enalaprilat clearance/creatinine clearance, 1.72 (P less than 0.05, difference from 1.0); enalaprilat clearance/inulin clearance, 1.85, (P less than 0.05, difference from 1.0). Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin and creatinine, suggesting that elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion.

Fosinopril: a new generation of angiotensin-converting enzyme inhibitors.

Fosinopril, the first agent in a new chemical class of phosphorus-containing angiotensin-converting enzyme (ACE) inhibitors, has unique pharmacologic properties. Fosinopril administration leads to complete inhibition of plasma ACE activity for 12-24 h. In patients with normal renal function, approximately equal amounts of the drug are eliminated via the hepatic and renal routes. With worsening renal function, increasing amounts of fosinopril are eliminated hepatically. This dual elimination allows for the administration of fosinopril using the same starting dosage to any patient, regardless of renal function. Fosinopril may provide end-organ protection against the effects of hypertension and antihypertensive therapy; this drug potentially protects the kidney by increasing renal functional reserve, while maintaining cardiac left ventricular performance. Moreover, despite marked blood reductions, cerebral blood flow is maintained. Controlled trials show that fosinopril in single daily doses of 10-40 mg is efficacious and safe for the long-term treatment of hypertension. At these doses, favorable responses were seen in up to 80% of patients. Fosinopril is equally effective in elderly as well as younger patients and works in black as well as in nonblack patients. The incidence of adverse events does not differ significantly between fosinopril- and placebo-treated patients. Fosinopril represents a clinically useful agent for the treatment of hypertension.

Pharmacokinetics of fosinopril in patients with various degrees of renal function

Single-dose kinetics of fosinopril, a new phosphorus-containing angiotensin-converting enzyme inhibitor and its active diacid, fosinoprilat, were investigated in patients with mild, moderate, or severe renal impairment and in those with normal renal function. After an intravenous dose of 14C-fosinoprilat (7.5 mg), total body clearance of fosinoprilat was significantly greater (p less than 0.05) in patients with normal renal function than in renally impaired patients but was not related to the degree of renal impairment in patients with creatinine clearance values of 11 to 72 ml/min/1.73 m2. Decreases in renal clearance were compensated for by increases in hepatic clearance, so that total clearance was maintained. After oral 14C-fosinopril (10 mg), plasma kinetics and bioavailability of fosinoprilat were similar for the three groups of renally impaired patients. The dual elimination of fosinoprilat by the liver and the kidney distinguishes fosinopril from other angiotensin-converting enzyme inhibitors.

Pharmacokinetics and Pharmacodynamics of Doxacurium in Young and Elderly Patients During Isoflurane Anesthesia

Preliminary disposition studies of the investigational, long-acting muscle relaxant doxacurium chloride (Nuromax) have demonstrated dual elimination by renal and hepatobiliary pathways, as well as slow hydrolysis by plasma cholinesterase. The present study compares the kinetics and dynamics of doxacurium in eight ASA physical status I or II elderly patients (67-72 yr of age) and eight ASA I or II young patients (22-49 yr of age). After institutionally approved written informed consent, kinetic and dynamic measurements were made after a 25-micrograms/kg bolus injection of doxacurium during 1.25 MAC nitrous oxide/oxygen/isoflurane anesthesia. Maximum twitch depression was similar in older patients (96.4% +/- 1.3%) to that in the young patients (96.6% +/- 1.8%). The time to achieve this level of block was significantly longer in the elderly than in the young (11.2 +/- 1.1 min versus 7.7 +/- 1.0 min, respectively). Recovery times to twitch heights of 5% and 25% of control tended to be prolonged and were more variable in the elderly (82.6 +/- 17.2 and 97.1 +/- 20.1 min, respectively) than in the young (54.8 +/- 9 and 67.5 +/- 8.2 min, respectively). Elimination half-life (96 +/- 20 min) and clearance (2.47 +/- 0.69 mL.kg-1.min-1) in the elderly patients were not statistically different from values found in the younger group. Volume of distribution at steady state in the elderly (220 +/- 80.2 mL/kg) was significantly larger than in the young (150 +/- 40.0 mL/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Performance Study of a Fuel Cell Pt‐on‐C Anode in Presence of CO and CO 2, and Calculation of Adsorption Parameters for CO Poisoning

A study was undertaken to measure polarization losses due to the presence of and in the fuel for a practical fuel cell Pt/C anode. A porous Pt anode (0.3 mg/cm2 Pt) was tested as a floating electrode in a half‐cell assembly to measure performance in 100 weight percent at 190°C in presence of , and , , and gas mixtures. The additional polarization loss over that of due to dilution followed closely the expected loss from the Nernst equation in the range of current density 0–300 mA/cm2. The combined loss due to poisoning by and the dilution by and was analyzed and found to be additive of the poisoning and dilution losses. The poisoning loss by was calculated by subtracting the dilution loss from the combined dilution and poisoning loss. Such data were found to be linearly dependent on the logarithm of ratio. This is consistent with poisoning by replacement of sites on the porous Pt electrode. The calculated values of surface coverage by ranged from 0.089 to 0.31 as the ratio varied from 0.01 to 0.025. The values of surface coverage were consistent with the dual site elimination model for the replacement of by molecules. The exchange current densities for oxidation varied from 309 to 142 mA/cm2 as the ratio changed from 0 to 0.025. By comparing the experimental isotherm for adsorption with the Temkin isotherm, the interaction parameter was calculated to be 3.83 kcal/mol, and the standard free energy of adsorption, −10.96 kcal/mol. The latter value indicated an adsorption of which is comparable to .

Changing Concepts and New Applications of Antibiotic Pharmacokinetics

Antibiotics with high protein binding have a lower percentage of free drug available for tissue penetration than antibiotics with lower protein binding. High protein binding, however, may have a beneficial effect on drug distribution. The smaller volume of distribution and reduced glomerular filtration of highly bound agents result in higher serum levels that are sustained longer. Although intermittent and continuous dosing regimens produce similar areas under the concentration-versus-time curves for serum and tissue, intermittent dosing produces higher peak and potentially earlier effective antibiotic levels at the site of infection. The excretion of certain antibiotic agents in the bile may be related to hepatic protein binding, high molecular weight, or unique structural features. Biliary excretion is important not only for bile concentrations but also for dosage modification. Antibiotics with dual elimination by the kidney and biliary tract require minimal dosage modification unless there is concomitant hepatic and renal dysfunction. The third-generation cephalosporins provide good examples of how protein binding, tissue penetration, and excretory mechanisms can be used to alter pharmacokinetics advantageously.