Cyclosporine bioavailability

Cyclosporine absorption is incomplete and somewhat erratic, although a microemulsion formulation improves its consistency and provides 20-30% bioavailability. Grapefruit juice increases cyclosporine bioavailability by as much as 62%. Cyclosporine is metabolized by CYP3Aand consequently is subject to a large number of drug interactions (see Chapters 55 and 66). 

Table 3 Measures of Cyclosporin Bioavailability and Hepatic Extraction After Oral Administration in the Presence or Absence of the CYP3A Inhibitors Ketoconazole and Erythromycin and the CYP3A Inducer Rifampin...

This active substance suppresses the release of interleukin 1 from monocytes and the synthesis of interleukins 2, 3 and 4 as well as of TNF-a from T helper cells T cell proliferation, macrophage stimulation and B cell activation are inhibited. Even at an early stage of the immune reaction, this leads to the suppression of both humoral and cellular immune responses. The body s bacterial defence is still not significantly influenced, as the phagocytic activity of the RES is barely inhibited by cyclosporine. Bioavailability is about 35% following oral application it is almost completely metabolized in the body and eliminated predominantly via the bile. Clin-... 

Fig. 1.3 An enzyme induction interaction. Rifampicin (600 mg daily plus isoniazid) increased the metabolism of ciclosporin in this patient thereto reducing the trough serum levels. He subsequently died because his heart transplant rejected (after Tronsp/ont Proc, 16, Van Buren D, Wideman CA, Ried M, Gibbons S, n Buren CT, Jarowenko M, Flechner SM, Frazier OH, Cool DA, Kahan BD. The antagonistic effect of ri mpidn upon cyclosporine bioavailability. 1642—5, Copyright Els ier (1984)).

Tsunoda SM, Harris RZ, Christians U, Velez RL, Freeman RB, Benet LZ, Warshaw A. Red wine decreases cyclosporine bioavailability. Clin Pharmacol T r (2001) 70,462-7. 

Figure 6 Relationship between cyclosporine bioavailability, given as AUC (integral of the blood concentration versus time curve), and dose after oral administration of ( ) a crude emulsion or (O) an 0/W microemulsion to healthy volunteers. (Adapted from Ref 47.)...

Drug absorption is highly variable in neonates and infants [21,22]. Older children appear to have absorption patterns similar to adults unless chronic illness or surgical procedures alter absorption. Differences in bile excretion, bowel length, and surface area probably contribute to the reduced bioavailability of cyclosporine seen in pediatric liver transplant patients [22a]. Impaired absorption has also been observed in severely malnourished children [22b]. A rapid GI transit time may contribute to the malabsorption of carbamazepine tablets, which has been reported in a child [23]. Selection of a more readily available bioavailable dosage form, such as chewable tablets or liquids, should be promoted for pediatric patients. 

A., Comparison of methods to calculate cyclosporine A bioavailability from consecutive oral and intravenous doses,/. Pharmacokinet. Biopharm. 

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. 

Christians U, First MR, Benet LZ (2000) Recommendations for bioequivalence testing of cyclosporine generics revisited. Ther Drug Monit 22 330-335 CPMP (2000) European Medicines Agency. Committee for Proprietary Medicinal Products. Note for guidance on the investigation on bioavailability and bioequivalence. CPMP/EWP/QWP/1401/98.http //www.emea.europa.eu/pdfs/human/qwp/140198en.pdf. Cited 30 Dec 2008... 

Absorption after oral administration is incomplete and variable. Its bioavailability ranges from 20% to 50%. Cyclosporine can also be given intravenously. Plasma protein binding is about 90% and cyclosporine also accumulates in red blood cells. It is extensively metabolized in the gastrointestinal mucosa and in the liver by the cytochrome P450-enzyme system. Its elimination half-life is about 19 hours in adults with a range of 10-27 hours and about 9 hours in children with a range of 3-19 hours. Over 30 different metabolites have been... 

Answer Cyclosporine is an immunosuppressant drug used to prevent transplant rejections. Though an oral formulation is available, it has low bioavailability (very httle reaches the systemic circulation as intact drug). Diltiazem will inhibit cytochrome P450 3A4 in the gut. CYP3A4 is the... 

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