Half-life quinolones

Elvitegravir (18, GS-9137, JTK-303, EVG) is the second IN strand transfer inhibitor to advance into phase III clinical trials (Figure 7). EVG was derived from the quinolone antibiotics which do not show IN activity [39-41]. Through careful optimization, this work resulted in EVG displaying enzyme and antiviral activity of 7.2 and 0.9 nM, respectively. EVG has moderate bioavailability in preclinical species (29 and 34%), low clearance (Qp 0.5 and l.OL/h/kg) and a moderate half-life of 2.3 and 5.2h in rats and dogs, respectively [42]. It is primarily metabolized via CYP450 oxidation and shows a marked increase in human exposure with RTV boosting. 

The quinolones are rapidly and almost completely absorbed after oral administration and are widely distributed in body tissues. Levels in extravascular spaces can often exceed serum levels. Levels lower than those found in serum occur in CSF, bone, and prostatic fluids. Ciprofloxacin and ofloxacin have been detected in breast milk and ofloxacin levels in ascites fluid are close to serum levels. Food ingestion does not affect bioavailability, which ranges from 50 to 95%. The half-life for most quinolones is 3 to 4 hours. 

Mecfianism of Action A quinolone-methanol compound structurally similar to quinine that destroys the asexual blood forms of malarial pafhogens, Plasmodium falciparum, P. vivax, P. malariae, P. ovale. Therapeutic Effect Inhibifs parasite growth. Pharmacokinetics Well absorbed from fhe gasfroinfesfinal (GI) tract. Protein binding 98%. Widely distributed, including cerebrospinal fluid (CSF). Metabolized in liver. Primarily excreted in urine. Half-life 21-22 days. 

Nalidixic acid is a highly protein bound oral quinolone (>90%), that undergoes major hepatic metabolism (80%) to active (hydroxynalidixic acid) and inactive metabolites [216]. The parent drug and its metabolites are rapidly excreted in the urine [217]. Most of the antibacterial effect is due to the biologically active hydroxynalidixic acid, which is 16 times more active than the parent compound. Nalidixic acid has a terminal half-life of about two hours. The drug does not accumulate in tissues even after prolonged administration the kidney is the only organ in which this may occur. Furthermore, nalidixic acid does not diffuse into prostatic fluid [214]. 

Tissue penetration, particularly in the kidneys and prostate, is excellent (Table 2). Those quinolones with longer half-life have smaller penetration ratios... 

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]. 

A study of the pharmacokinetics of orally administered ciprofloxacin in elderly (63-76 years) and young volunteers (22-34 years) without renal impairment, revealed in the elderly group a decreased renal clearance of the quinolone with no differences detected in the terminal half-life (3.5 hours). This was accompanied, however, by a surprising increase in the absolute availability of the drug [226]. The authors cautioned about the need for a reduction of oral dosage of ciprofloxacin in the elderly population. 

Indications Psychosis, manic-depressive disorders Category Antipsychotic, phenothiazine Muscarinic antagonist Half-life initial 2 hours terminal 30 hours Clinically important, potentially hazardous interactions with alcohol, antihistamines, arsenic, chlorpheniramine, dofetilide, epinephrine, evening primrose, guanethidine, mivacurium, quinolones, sparfloxacin... 

Indications Various infections caused by susceptible organisms Category Antibiotic, quinolone Half-life 4 hours... 

Table 38.2. Pharmacokinetic Properties for Selective Quinolones Drug Bioavailability (%)Protein Binding (%)Half-life (hours)...

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