Table 3.
Effect of drugs on the biotransformation of CMV423 by human liver microsomes. Twenty-six drugs likely to be coadministered with CMV423 in the clinic, were tested in coincubation and preincubation experiments at a single high concentration (as described in the Methods). The in vivo Cmax of each drug is given, in parenthesis, for comparison. The results are expressed as a percentage of controls (vehicles only). The drugs have been classified in four groups. 1): drugs giving less than 25% inhibition and no activation. 2): drugs giving between 25% and 50% inhibition. 3): drugs giving more than 50% inhibition and 4): drugs giving more than 60% activation. In each group, drugs are listed in alphabetical order. Each value represents the mean of a triplicate assay. Coefficients of variation were below 20%.
| Drug name | Tested concentration (Cmaxin vivo) in µm | CMV423 (10 µm) Effect on RPR 127025 formation (%) coincubation | preincubation | RPR 127025 (10 µm) Effect on RPR 123830 formation (%) coincubation | preincubation |
|---|---|---|---|---|---|
| Group 1 | |||||
| Acyclovir | 1000 (10) | + 20 | + 18 | + 23 | + 19 |
| AZT | 1000 (7) | + 8 | −2 | −2 | −13 |
| Cyclosporin A | 62.5 (0.5) | −8 | −6 | + 10 | −13 |
| Desogestrel | 125 (unknown) | + 5 | + 8 | + 8 | + 54 |
| Didanosine | 1000 (5) | −10 | −13 | + 38 | + 22 |
| Foscarnet | 1000 (46) | + 4 | 0 | −24 | + 5 |
| Lamivudine | 1000 (6) | −21 | + 17 | + 3 | + 6 |
| Nelfinavir | 125 (4) | + 19 | −4 | + 26 | −17 |
| Norgestimate | 125 (unknown) | + 34 | −22 | + 28 | + 14 |
| Saquinavir | 62.5 (0.4) | + 11 | −23 | −9 | + 21 |
| Stavudine | 1000 (4) | −1 | + 6 | + 5 | + 40 |
| Group 2 | |||||
| Ethinyl estradiol | 62.5 (0.0005) | −9 | −27 | −7 | −38 |
| Indinavir | 1000 (122) | −34 | −21 | −29 | −24 |
| Itraconazole | 62.5 (1) | −17 | −15 | −23 | −34 |
| Methadone | 250 (4) | + 4 | −39 | + 34 | + 60 |
| Paracetamol | 1000 (500) | −2 | −32 | −15 | + 7 |
| Ritonavir | 1000 (8) | −40 | −28 | −43 | −36 |
| Theophylline | 1000 (110) | −21 | −34 | −31 | −26 |
| Warfarin | 1000 (30) | −23 | −41 | −27 | −12 |
| Group 3 | |||||
| Cimetidine | 1000 (4) | −50 | −65 | −53 | −51 |
| Enoxacine | 1000 (6) | −52 | −48 | −20 | −17 |
| Imipramine | 1000 (0.4) | −82 | −90 | −77 | −81 |
| Group 4 | |||||
| Chlormadinone | 62.5 (unknown) | + 81 | + 126 | + 207 | + 187 |
| Ethynodiol | 62.5 (unknown) | + 113 | + 80 | + 136 | + 110 |
| Norethindrone | 250 (0.05) | + 114 | + 85 | + 58 | + 81 |
| (–) Norgestrel | 250 (0.008) | + 72 | + 4 | + 151 | + 171 |