Oral clearance

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

Mihaly et al. [127] examined the pharmacokinetics of primaquine in healthy volunteers who received single oral doses of 15, 30, and 45 mg of the drug, on separate occasions. Each subject received an intravenous tracer dose of 14C-prima-quine (7.5 pCi), simultaneously with 45 mg oral dose. Absorption of primaquine was virtually complete with a mean absorption bioavailability of 0.96. Elimination half-life, oral clearance, and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size or route of administration. 

The 3 -hydroxycotinine/cotinine ratio (3HC/cotinine) in plasma and saliva has been evaluated as a non-invasive probe for CYP2A6 activity (Dempsey et al. 2004). The ratio was highly correlated with oral clearance of nicotine and the oral clearance and half-life of cotinine. Correlation coefficients of oral nicotine and cotinine clearances with plasma 3 -hydroxycotinine/cotinine ratios were 0.78 and 0.63, respectively, at 6 h after oral nicotine dosing. 

Log D7.4 Affinity (nM) Absorption (%) Oral clearance (unbound) mL min kg Volume of distribution (unbound) Lkg Half-life (h)... 

Oral unbound clearance (i.e. oral clearance correct for free fraction)... 

When considering the Hkely pharmacokinetic profile of a novel compound in man, it is important to recognize the variability that may be encountered in the cHnical setting. Animal pharmacokinetic studies are generally conducted in inbred animal colonies that tend to show minimal inter-subject variabiHty. The human population contains a diverse genetic mix, without the additional variability introduced by age, disease states, environmental factors and co-medications. Hence any estimate of pharmacokinetic behaviour in man must be tempered by the expected inherent variability. For compounds with high metabolic clearance (e. g. midazolam), inter-individual variability in metabolic clearance can lead to greater than 10-fold variation in oral clearance and hence systemic exposure [1]. 

Elderly Oral clearance was reduced in the elderly compared with the younger subjects. Caution is indicated in administering mirtazapine to elderly patients. Pregnancy Category B (maprotiline) Category C (mirtazapine). 

Hepatic function impairment Zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. Consequently, the oral clearance of zaleplon was reduced by 70% and 87% in compensated and decompensated cirrhotic patients, respectively. 

Eideriy Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in Ccr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function. 

Elderly Pramipexole total oral clearance was approximately 30% lower in subjects older than 65 years of age compared with younger subjects, because of a decline in pramipexole renal clearance. The incidence of confusion and hallucinations appears to increase with age. Serious adverse events were more common in older patients (ie, falling, cardiovascular events, respiratory disorders, Gl events). 

Gender The estimated apparent oral clearance of rifapentine for males and females was approximately 2.51 and 1.69 L/h, respectively. The clinical significance of the difference in the estimated apparent oral clearance is not known. 

Excretion - Less than 3% of the lopinavir dose is excreted unchanged in the urine. The half-life of lopinavir over a 12-hour dosing interval averaged 5 to 6 hours the apparent oral clearance (CL/F) of lopinavir is 6 to 7 L/h. 

Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes 3A4 and 2B6. The pharmacokinetics of autoinduction are characterized by an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to 2 to 4 weeks of dosing with 200 to 400 mg/day. Auto-induction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately 25 to 30 hours following multiple dosing with 200 to 400 mg/day. 

Simvastatin increased oral clearance of nevirapine with... 

Jerling, M., Dahl, M.-L., °Aberg-Wistedt, A., Liljenberg, B., Lan-dell, N.-E., Bertilsson, L., and Sjoqvist, F. (1996) The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clin Pharmacol Ther 59 423-428. 

Study Study phase Midazolam systemic clearance (L/hr) Midazolam oral clearance (L/hr) Midazolam bioavailability (%)... 

Dresser et al. administered St. John s wort (LI 160 300 mg t.i.d.) to 20 ethnically diverse individuals and observed a 44% increase in the systemic clearance of midazolam (Table 3) (98). In contrast, the oral clearance of midazolam was increased 1.7-fold (Table 3). The combined changes in midazolam disposition resulted in a significant reduction in the oral bioavailability of midazolam (Table 3). Gurley et al. examined the one-hour 1-hydroxymidazolam-to-midazolam serum ratio and concluded that St. John s wort administration for 28 days resulted in a significant increase in the ratio, which is indicative of CYP3A4 induction (100). 

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