In vitro studies of the effects of HAART drugs and excipients on activity of digestive enzymes.
OBJECTIVE
Side effects of diarrhea and steatorrhea diminish the therapeutic value of highly active antiretroviral therapy (HAART). We report in vitro studies of the effect of HAART drugs on the activity of pancrelipase, trypsin, and enterokinase and restoration of activity by subsequent addition of excess pancrelipase or colipase.


METHODS
Commercial formulations of sixteen HAART drug formulations with solvent and four excipients were mixed with substrate. Activity of pancrelipase was recorded after addition of the enzyme; restoration of activity was monitored after addition of excess pancrelipase or colipase to the reaction mixture.


RESULTS
Five protease inhibitors (Agenerase solution, Agenerase capsules, Norvir, Viracept, Kaletra, and Fortovase) and the excipient TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) inhibited lipase significantly at or below physiological concentrations. Neither nucleoside reverse transcriptase inhibitors nor non-nucleoside reverse transcriptase inhibitors showed significant lipase inhibition at physiological levels. Addition of excess pancrelipase to the medium completely reversed inhibition by Agenerase, Fortovase, Norvir, and TPGS and reactivated lipase; it diminished inhibition by Kaletra and Viracept but did not completely restore activity. Addition of colipase reversed inhibition by Agenerase solution, Agenerase capsules, and TPGS; inhibition by Kaletra and Fortovase recovered slightly. No compounds tested inhibited trypsin or enterokinase.


CONCLUSIONS
These results justify evaluating protocols involving coadministration of buffered pancrelipase with protease inhibitors to reduce or eliminate diarrhea and steatorrhea in individuals being treated for HIV.
Wignot
Terese M
TM
Chemistry Department, Wilkes University, Wilkes Barre, Pennsylvania 18766, USA.
Stewart
Roger P
RP
Schray
Keith J
KJ
Das
Simantini
S
Sipos
Tibor
T
D023241:Antiretroviral Therapy, Highly Active; D005079:Excipients; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors; D006801:Humans; D019888:Nelfinavir; D018894:Reverse Transcriptase Inhibitors; D019258:Saquinavir
D005079:Excipients; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019888:Nelfinavir; D019258:Saquinavir