Renal clearance orally administered dose

Metabolism/Excretion Zalcitabine is phosphorylated intracellularly to zalcitabine triphosphate, the active substrate for HIV-reverse transcriptase. Concentrations of zalcitabine triphosphate are too low for quantitation. Metabolism has not been fully evaluated. Zalcitabine does not appear to undergo a significant degree of metabolism by the liver. Renal excretion appears to be the primary route of elimination, and accounted for approximately 70% of an orally administered dose within 24 hours after dosing. The mean elimination half-life is 2 hours. Total body clearance following an IV dose averages 285 mL/min. Less than 10% of a dose... 

Renal clearance of an orally administered dose of a drug... 

The good bioavailability of orally administered ciprofloxacin obviates the need for the more expensive intravenous formulation. I.v. ciprofloxacin is only given to patients who have severe sepsis or severe nausea and vomiting. Ciprofloxacin s elimination is 50% hepatic and 50% renal. Therefore, dose reduction is recommended only in case creatinine clearance drops to < 10 ml/min. Prevention of food-borne disease requires efforts at many levels. Monitoring safety of food processing, vector control, surveillance of outbreaks, education on personal hygiene and improving sanitation and access to safe water supplies are all necessary measures to reduce the incidence of GTI. 

Oral verapamil has been shown to increase peak plasma levels, prolong the terminal half-life, and increase the volume of distribution at steady state of doxorubicin (282). Gigante et al. (283) performed similar studies in which the pharmacokinetics of doxorubicin in combination with verapamil given at high doses intravenously were followed for 17 patients with advanced neoplasms. The steady-state concentration and systemic and renal clearances were found to be statistically similar for various doses of verapamil and doxorubicin, and for doxorubicin administered alone. 

A. Pharmacokinetics Pamidronate is administered intravenously. All of the other bisphosphonates are orally active, although less than ten percent of the administered dose is absorbed. Food significantly interferes with absorption. Bisphosphonates should be administered with six to eight ounces of water at least one hour before eating breakfast. The bisphosphonates are rapidly cleared from the plasma, primarily because they avidly bind to hydroxyapatite mineral of bone. Once bound to bone they are cleared over a period of months to years. Elimination from the body is solely through renal clearance, and the bisphosphonates should not be given to individuals with severe renal impairment. 

The bioavailability of oral or parenterally administered ciprofloxacin was not affected in patients and rats with renal insufficiency [222]. The renal clearance of the quinolone, however, was reduced resulting in a prolonged half-life [223-225]. Thus, a reduction of 50% in the dose of ciprofloxacin has been recommended when the creatinine clearance is between 10 and 30 ml/ min/1.73 m [224]. Of interest, it has been suggested that there may be a compensatory transin-testinal elimination of ciprofloxacin in patients and rats with reduced renal function [224, 225]. 

Methotrexate is readily filtered by the kidneys, and renal clearance is influence by both tubular secretion [139, 140, 141, 142] and tubular reabsorption [142]. Intravenous administration of methotrexate 140-350 mg/kg [<6h infusion] results in 70-94% of the dose appearing in the urine over 24 h [143]. In contrast, when methotrexate is administered as a 24-h continuous infusion, 60% of the dose is excreted in the mine during the 24-h infusion [144]. Approximately 10% of the dose is excreted in the urine as 7-hydroxymethotrexate [143,144]. The 7-hydroxy metabohte is important since it may contribute to the renal toxicity of methotrexate [148] and this moiety becomes a significant metabolite when methotrexate doses are 50 mg/kg or greater [145]. Following oral administration of methotrexate a lesser fraction of the dose is recovered in the urine than following intravenous administration [141]. This may reflect the dose-dependent incomplete absorption of methotrexate [141,146,147]. Methotrexate is highly bound to plasma proteins. 

Oral administration of etoposide results in variable absorption that averages about 50%. After intravenous injection, peak plasma concentrations of 30 pg/mL are achieved there is a biphasic pattern of clearance with a terminal half-hfe of about 6 to 8 hours in patients with normal renal function. Approximately 40% of an administered dose is excreted intact in the urine, hi patients with compromised renal function, dosage should be reduced in proportion to the reduction in... 

The oral bioavailability of zalcitabine is greater than 80%, and 60 to 80% of the parent compound is recovered unchanged in the urine. Food has a negligible effect on oral bioavailability. Clearance is greatly diminished in patients with compromised renal function, and daily doses should be reduced in this population. The half-life of intracellular dideoxycytidine 5 -triphosphate is estimated to be 2 to 3 hours. It is therefore recommended that zalcitabine be administered every 8 hours in patients with normal renal function. The CSF-plasma concentration ratio ranges from 0.09 to 0.37, although the clinical significance of CSF penetration is not known. 

The precursor of bleomycin, phleomycin, was too nephrotoxic for development and the search for less toxic analogues resulted in the discovery of bleomycin [4, 8]. The major dose-limiting toxicity is pulmonary fibrosis and other serious toxicides noted have been hyperpyrexia, acute hypotensive responses and mucositis. The pulmonary toxicity appears to be dose-related and has led to fatalities. Bleomycin is administered as the metal-free chelate and is absorbed when administered orally excretion is mainly by renal clearance. 

FIGURE 4.5 Multicompartment system used to model the kinetics of NAPA absorption, distribution, and elimination. NAPA labeled with was injected intravenously (IV) to define the kinetics of NAPA disposition. NAPA distribution from intravascular space (Vq) to fast (Vp) and slow (Vg) equilibrating peripheral compartments is characterized by the intercompartmental clearances CLp and CLg. NAPA is cleared from the body by both renal (CLj ) and nonrenal (CLjyj ) mechanisms. A NAPA tablet was administered orally with the intravenous dose to analyze the kinetics of NAPA absorption from the gastrointestinal (GI) tract. After an initial delay that consisted of a time lag (not shown) and presumed delivery of NAPA to the small bowel (feg), the rate and extent of NAPA absorption were determined by ka and ko, as described in the text. (Reproduced with permission from Atkinson AJ, Jr. et al. Clin Pharmacol Ther 1989 46 182-9.)... 

Excretion studies93 with the 14C-labelled muscle relaxant 44 (C-14CH2-N label) in man after administration of a single oral dose of 50 and 100 mg have shown that this compound is rapidly and completely absorbed but is extensively metabolized before reaching the systemic circulation. The administered radioactivity was found to be completely recovered within 24 h after dosing, predominantly in the urine—with a renal/faecal clearance ratio of about 96 4. Information concerning the structure of the metabolites is not available. 

---